A glycogen synthase kinase that was originally described as a key enzyme involved in glycogen metabolism. It regulates a diverse array of functions such as CELL DIVISION, microtubule function and APOPTOSIS.
A class of protein-serine-threonine kinases that was originally found as one of the three types of kinases that phosphorylate GLYCOGEN SYNTHASE. Glycogen synthase kinases along with CA(2+)-CALMODULIN DEPENDENT PROTEIN KINASES and CYCLIC AMP-DEPENDENT PROTEIN KINASES regulate glycogen synthase activity.
An enzyme that catalyzes the transfer of D-glucose from UDPglucose into 1,4-alpha-D-glucosyl chains. EC 2.4.1.11.
A salt of lithium that has been used experimentally as an immunomodulator.
The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.
A CALMODULIN-dependent enzyme that catalyzes the phosphorylation of proteins. This enzyme is also sometimes dependent on CALCIUM. A wide range of proteins can act as acceptor, including VIMENTIN; SYNAPSINS; GLYCOGEN SYNTHASE; MYOSIN LIGHT CHAINS; and the MICROTUBULE-ASSOCIATED PROTEINS. (From Enzyme Nomenclature, 1992, p277)
Glycogen stored in the liver. (Dorland, 28th ed)
A multi-functional catenin that participates in CELL ADHESION and nuclear signaling. Beta catenin binds CADHERINS and helps link their cytoplasmic tails to the ACTIN in the CYTOSKELETON via ALPHA CATENIN. It also serves as a transcriptional co-activator and downstream component of WNT PROTEIN-mediated SIGNAL TRANSDUCTION PATHWAYS.
Phosphotransferases that catalyzes the conversion of 1-phosphatidylinositol to 1-phosphatidylinositol 3-phosphate. Many members of this enzyme class are involved in RECEPTOR MEDIATED SIGNAL TRANSDUCTION and regulation of vesicular transport with the cell. Phosphatidylinositol 3-Kinases have been classified both according to their substrate specificity and their mode of action within the cell.
A protein-serine-threonine kinase that is activated by PHOSPHORYLATION in response to GROWTH FACTORS or INSULIN. It plays a major role in cell metabolism, growth, and survival as a core component of SIGNAL TRANSDUCTION. Three isoforms have been described in mammalian cells.
An enzyme that catalyzes the degradation of GLYCOGEN in animals by releasing glucose-1-phosphate from the terminal alpha-1,4-glycosidic bond. This enzyme exists in two forms: an active phosphorylated form ( PHOSPHORYLASE A) and an inactive un-phosphorylated form (PHOSPHORYLASE B). Both a and b forms of phosphorylase exist as homodimers. In mammals, the major isozymes of glycogen phosphorylase are found in muscle, liver and brain tissue.
A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.
The intracellular transfer of information (biological activation/inhibition) through a signal pathway. In each signal transduction system, an activation/inhibition signal from a biologically active molecule (hormone, neurotransmitter) is mediated via the coupling of a receptor/enzyme to a second messenger system or to an ion channel. Signal transduction plays an important role in activating cellular functions, cell differentiation, and cell proliferation. Examples of signal transduction systems are the GAMMA-AMINOBUTYRIC ACID-postsynaptic receptor-calcium ion channel system, the receptor-mediated T-cell activation pathway, and the receptor-mediated activation of phospholipases. Those coupled to membrane depolarization or intracellular release of calcium include the receptor-mediated activation of cytotoxic functions in granulocytes and the synaptic potentiation of protein kinase activation. Some signal transduction pathways may be part of larger signal transduction pathways; for example, protein kinase activation is part of the platelet activation signal pathway.
Phenols substituted in any position by an amino group.
A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.
A class of glucosyltransferases that catalyzes the degradation of storage polysaccharides, such as glucose polymers, by phosphorolysis in animals (GLYCOGEN PHOSPHORYLASE) and in plants (STARCH PHOSPHORYLASE).
A scaffolding protein that is a critical component of the axin signaling complex which binds to ADENOMATOUS POLYPOSIS COLI PROTEIN; GLYCOGEN SYNTHASE KINASE 3; and CASEIN KINASE I.
Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.
Agents that inhibit PROTEIN KINASES.
Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.
A non-essential amino acid occurring in natural form as the L-isomer. It is synthesized from GLYCINE or THREONINE. It is involved in the biosynthesis of PURINES; PYRIMIDINES; and other amino acids.
An intracellular signaling system involving the MAP kinase cascades (three-membered protein kinase cascades). Various upstream activators, which act in response to extracellular stimuli, trigger the cascades by activating the first member of a cascade, MAP KINASE KINASE KINASES; (MAPKKKs). Activated MAPKKKs phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES which in turn phosphorylate the MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs). The MAPKs then act on various downstream targets to affect gene expression. In mammals, there are several distinct MAP kinase pathways including the ERK (extracellular signal-regulated kinase) pathway, the SAPK/JNK (stress-activated protein kinase/c-jun kinase) pathway, and the p38 kinase pathway. There is some sharing of components among the pathways depending on which stimulus originates activation of the cascade.
An element in the alkali metals family. It has the atomic symbol Li, atomic number 3, and atomic weight [6.938; 6.997]. Salts of lithium are used in treating BIPOLAR DISORDER.
A primary source of energy for living organisms. It is naturally occurring and is found in fruits and other parts of plants in its free state. It is used therapeutically in fluid and nutrient replacement.
Microtubule-associated proteins that are mainly expressed in neurons. Tau proteins constitute several isoforms and play an important role in the assembly of tubulin monomers into microtubules and in maintaining the cytoskeleton and axonal transport. Aggregation of specific sets of tau proteins in filamentous inclusions is the common feature of intraneuronal and glial fibrillar lesions (NEUROFIBRILLARY TANGLES; NEUROPIL THREADS) in numerous neurodegenerative disorders (ALZHEIMER DISEASE; TAUOPATHIES).
Wnt proteins are a large family of secreted glycoproteins that play essential roles in EMBRYONIC AND FETAL DEVELOPMENT, and tissue maintenance. They bind to FRIZZLED RECEPTORS and act as PARACRINE PROTEIN FACTORS to initiate a variety of SIGNAL TRANSDUCTION PATHWAYS. The canonical Wnt signaling pathway stabilizes the transcriptional coactivator BETA CATENIN.
A 51-amino acid pancreatic hormone that plays a major role in the regulation of glucose metabolism, directly by suppressing endogenous glucose production (GLYCOGENOLYSIS; GLUCONEOGENESIS) and indirectly by suppressing GLUCAGON secretion and LIPOLYSIS. Native insulin is a globular protein comprised of a zinc-coordinated hexamer. Each insulin monomer containing two chains, A (21 residues) and B (30 residues), linked by two disulfide bonds. Insulin is used as a drug to control insulin-dependent diabetes mellitus (DIABETES MELLITUS, TYPE 1).
Benzopyrroles with the nitrogen at the number one carbon adjacent to the benzyl portion, in contrast to ISOINDOLES which have the nitrogen away from the six-membered ring.
Products of proto-oncogenes. Normally they do not have oncogenic or transforming properties, but are involved in the regulation or differentiation of cell growth. They often have protein kinase activity.
Established cell cultures that have the potential to propagate indefinitely.
An ester of glucose with phosphoric acid, made in the course of glucose metabolism by mammalian and other cells. It is a normal constituent of resting muscle and probably is in constant equilibrium with fructose-6-phosphate. (Stedman, 26th ed)
Cells propagated in vitro in special media conducive to their growth. Cultured cells are used to study developmental, morphologic, metabolic, physiologic, and genetic processes, among others.
A serine-threonine kinase that plays important roles in CELL DIFFERENTIATION; CELL MIGRATION; and CELL DEATH of NERVE CELLS. It is closely related to other CYCLIN-DEPENDENT KINASES but does not seem to participate in CELL CYCLE regulation.
A group of protein-serine-threonine kinases that was originally identified as being responsible for the PHOSPHORYLATION of CASEINS. They are ubiquitous enzymes that have a preference for acidic proteins. Casein kinases play a role in SIGNAL TRANSDUCTION by phosphorylating a variety of regulatory cytoplasmic and regulatory nuclear proteins.
Identification of proteins or peptides that have been electrophoretically separated by blot transferring from the electrophoresis gel to strips of nitrocellulose paper, followed by labeling with antibody probes.
Descriptions of specific amino acid, carbohydrate, or nucleotide sequences which have appeared in the published literature and/or are deposited in and maintained by databanks such as GENBANK, European Molecular Biology Laboratory (EMBL), National Biomedical Research Foundation (NBRF), or other sequence repositories.
The order of amino acids as they occur in a polypeptide chain. This is referred to as the primary structure of proteins. It is of fundamental importance in determining PROTEIN CONFORMATION.
Contractile tissue that produces movement in animals.
A group of enzymes that are dependent on CYCLIC AMP and catalyze the phosphorylation of SERINE or THREONINE residues on proteins. Included under this category are two cyclic-AMP-dependent protein kinase subtypes, each of which is defined by its subunit composition.
Derivatives of the steroid androstane having two double bonds at any site in any of the rings.
The uptake of naked or purified DNA by CELLS, usually meaning the process as it occurs in eukaryotic cells. It is analogous to bacterial transformation (TRANSFORMATION, BACTERIAL) and both are routinely employed in GENE TRANSFER TECHNIQUES.
Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.
A eukayrotic protein serine-threonine phosphatase subtype that dephosphorylates a wide variety of cellular proteins. The enzyme is comprised of a catalytic subunit and regulatory subunit. Several isoforms of the protein phosphatase catalytic subunit exist due to the presence of multiple genes and the alternative splicing of their mRNAs. A large number of proteins have been shown to act as regulatory subunits for this enzyme. Many of the regulatory subunits have additional cellular functions.
Major constituent of the cytoskeleton found in the cytoplasm of eukaryotic cells. They form a flexible framework for the cell, provide attachment points for organelles and formed bodies, and make communication between parts of the cell possible.
A group of enzymes removing the SERINE- or THREONINE-bound phosphate groups from a wide range of phosphoproteins, including a number of enzymes which have been phosphorylated under the action of a kinase. (Enzyme Nomenclature, 1992)
The process in which substances, either endogenous or exogenous, bind to proteins, peptides, enzymes, protein precursors, or allied compounds. Specific protein-binding measures are often used as assays in diagnostic assessments.
An serine-threonine protein kinase that requires the presence of physiological concentrations of CALCIUM and membrane PHOSPHOLIPIDS. The additional presence of DIACYLGLYCEROLS markedly increases its sensitivity to both calcium and phospholipids. The sensitivity of the enzyme can also be increased by PHORBOL ESTERS and it is believed that protein kinase C is the receptor protein of tumor-promoting phorbol esters.
A subtype of striated muscle, attached by TENDONS to the SKELETON. Skeletal muscles are innervated and their movement can be consciously controlled. They are also called voluntary muscles.
A family of protein serine/threonine kinases which act as intracellular signalling intermediates. Ribosomal protein S6 kinases are activated through phosphorylation in response to a variety of HORMONES and INTERCELLULAR SIGNALING PEPTIDES AND PROTEINS. Phosphorylation of RIBOSOMAL PROTEIN S6 by enzymes in this class results in increased expression of 5' top MRNAs. Although specific for RIBOSOMAL PROTEIN S6 members of this class of kinases can act on a number of substrates within the cell. The immunosuppressant SIROLIMUS inhibits the activation of ribosomal protein S6 kinases.
The rate dynamics in chemical or physical systems.
A large lobed glandular organ in the abdomen of vertebrates that is responsible for detoxification, metabolism, synthesis and storage of various substances.
An enzyme that catalyzes the conversion of phosphorylated, inactive glycogen synthase D to active dephosphoglycogen synthase I. EC 3.1.3.42.
A casein kinase that was originally described as a monomeric enzyme with a molecular weight of 30-40 kDa. Several ISOENZYMES of casein kinase I have been found which are encoded by separate genes. Many of the casein kinase I isoenzymes have been shown to play distinctive roles in intracellular SIGNAL TRANSDUCTION.
A mitogen-activated protein kinase subfamily that regulates a variety of cellular processes including CELL GROWTH PROCESSES; CELL DIFFERENTIATION; APOPTOSIS; and cellular responses to INFLAMMATION. The P38 MAP kinases are regulated by CYTOKINE RECEPTORS and can be activated in response to bacterial pathogens.
A cell line derived from cultured tumor cells.
One of the mechanisms by which CELL DEATH occurs (compare with NECROSIS and AUTOPHAGOCYTOSIS). Apoptosis is the mechanism responsible for the physiological deletion of cells and appears to be intrinsically programmed. It is characterized by distinctive morphologic changes in the nucleus and cytoplasm, chromatin cleavage at regularly spaced sites, and the endonucleolytic cleavage of genomic DNA; (DNA FRAGMENTATION); at internucleosomal sites. This mode of cell death serves as a balance to mitosis in regulating the size of animal tissues and in mediating pathologic processes associated with tumor growth.
A subgroup of mitogen-activated protein kinases that activate TRANSCRIPTION FACTOR AP-1 via the phosphorylation of C-JUN PROTEINS. They are components of intracellular signaling pathways that regulate CELL PROLIFERATION; APOPTOSIS; and CELL DIFFERENTIATION.
Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.
A key intermediate in carbohydrate metabolism. Serves as a precursor of glycogen, can be metabolized into UDPgalactose and UDPglucuronic acid which can then be incorporated into polysaccharides as galactose and glucuronic acid. Also serves as a precursor of sucrose lipopolysaccharides, and glycosphingolipids.
A family of F-box domain proteins that contain sequences that are homologous to the beta subunit of transducin (BETA-TRANSDUCIN). They play an important role in the protein degradation pathway by becoming components of SKP CULLIN F-BOX PROTEIN LIGASES, which selectively act on a subset of proteins including beta-catenin and IkappaBbeta.
A group of inherited metabolic disorders involving the enzymes responsible for the synthesis and degradation of glycogen. In some patients, prominent liver involvement is presented. In others, more generalized storage of glycogen occurs, sometimes with prominent cardiac involvement.
A proline-directed serine/threonine protein kinase which mediates signal transduction from the cell surface to the nucleus. Activation of the enzyme by phosphorylation leads to its translocation into the nucleus where it acts upon specific transcription factors. p40 MAPK and p41 MAPK are isoforms.
A PROTEIN-TYROSINE KINASE family that was originally identified by homology to the Rous sarcoma virus ONCOGENE PROTEIN PP60(V-SRC). They interact with a variety of cell-surface receptors and participate in intracellular signal transduction pathways. Oncogenic forms of src-family kinases can occur through altered regulation or expression of the endogenous protein and by virally encoded src (v-src) genes.
The phosphoric acid ester of serine.
The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.
Small double-stranded, non-protein coding RNAs (21-31 nucleotides) involved in GENE SILENCING functions, especially RNA INTERFERENCE (RNAi). Endogenously, siRNAs are generated from dsRNAs (RNA, DOUBLE-STRANDED) by the same ribonuclease, Dicer, that generates miRNAs (MICRORNAS). The perfect match of the siRNAs' antisense strand to their target RNAs mediates RNAi by siRNA-guided RNA cleavage. siRNAs fall into different classes including trans-acting siRNA (tasiRNA), repeat-associated RNA (rasiRNA), small-scan RNA (scnRNA), and Piwi protein-interacting RNA (piRNA) and have different specific gene silencing functions.
A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.
A 44-kDa extracellular signal-regulated MAP kinase that may play a role the initiation and regulation of MEIOSIS; MITOSIS; and postmitotic functions in differentiated cells. It phosphorylates a number of TRANSCRIPTION FACTORS; and MICROTUBULE-ASSOCIATED PROTEINS.
A superfamily of PROTEIN-SERINE-THREONINE KINASES that are activated by diverse stimuli via protein kinase cascades. They are the final components of the cascades, activated by phosphorylation by MITOGEN-ACTIVATED PROTEIN KINASE KINASES, which in turn are activated by mitogen-activated protein kinase kinase kinases (MAP KINASE KINASE KINASES).
An enzyme that catalyzes the conversion of ATP and PHOSPHORYLASE B to ADP and PHOSPHORYLASE A.
A serine-threonine protein kinase family whose members are components in protein kinase cascades activated by diverse stimuli. These MAPK kinases phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES and are themselves phosphorylated by MAP KINASE KINASE KINASES. JNK kinases (also known as SAPK kinases) are a subfamily.
Proteins prepared by recombinant DNA technology.
The level of protein structure in which combinations of secondary protein structures (alpha helices, beta sheets, loop regions, and motifs) pack together to form folded shapes called domains. Disulfide bridges between cysteines in two different parts of the polypeptide chain along with other interactions between the chains play a role in the formation and stabilization of tertiary structure. Small proteins usually consist of only one domain but larger proteins may contain a number of domains connected by segments of polypeptide chain which lack regular secondary structure.
Diffusible gene products that act on homologous or heterologous molecules of viral or cellular DNA to regulate the expression of proteins.
A strain of albino rat used widely for experimental purposes because of its calmness and ease of handling. It was developed by the Sprague-Dawley Animal Company.
Immunologic method used for detecting or quantifying immunoreactive substances. The substance is identified by first immobilizing it by blotting onto a membrane and then tagging it with labeled antibodies.
Protein kinases that control cell cycle progression in all eukaryotes and require physical association with CYCLINS to achieve full enzymatic activity. Cyclin-dependent kinases are regulated by phosphorylation and dephosphorylation events.
Enzyme that catalyzes the first step of the tricarboxylic acid cycle (CITRIC ACID CYCLE). It catalyzes the reaction of oxaloacetate and acetyl CoA to form citrate and coenzyme A. This enzyme was formerly listed as EC 4.1.3.7.
A phosphatidylinositol 3-kinase that catalyzes the conversion of 1-phosphatidylinositol into 1-phosphatidylinositol 3-phosphate.
The parts of a macromolecule that directly participate in its specific combination with another molecule.
An essential amino acid occurring naturally in the L-form, which is the active form. It is found in eggs, milk, gelatin, and other proteins.
All of the processes involved in increasing CELL NUMBER including CELL DIVISION.
A ubiquitous casein kinase that is comprised of two distinct catalytic subunits and dimeric regulatory subunit. Casein kinase II has been shown to phosphorylate a large number of substrates, many of which are proteins involved in the regulation of gene expression.
The active form of GLYCOGEN PHOSPHORYLASE that is derived from the phosphorylation of PHOSPHORYLASE B. Phosphorylase a is deactivated via hydrolysis of phosphoserine by PHOSPHORYLASE PHOSPHATASE to form PHOSPHORYLASE B.
Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.
The phosphoric acid ester of threonine. Used as an identifier in the analysis of peptides, proteins, and enzymes.
Elements of limited time intervals, contributing to particular results or situations.
Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control (induction or repression) of gene action at the level of transcription or translation.
A T-cell factor that plays an essential role in EMBRYONIC DEVELOPMENT.
A family of ribosomal protein S6 kinases that are considered the major physiological kinases for RIBOSOMAL PROTEIN S6. Unlike RIBOSOMAL PROTEIN S6 KINASES, 90KDa the proteins in this family are sensitive to the inhibitory effects of RAPAMYCIN and contain a single kinase domain. They are referred to as 70kDa proteins, however ALTERNATIVE SPLICING of mRNAs for proteins in this class also results in 85kDa variants being formed.
The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.
Strains of mice in which certain GENES of their GENOMES have been disrupted, or "knocked-out". To produce knockouts, using RECOMBINANT DNA technology, the normal DNA sequence of the gene being studied is altered to prevent synthesis of a normal gene product. Cloned cells in which this DNA alteration is successful are then injected into mouse EMBRYOS to produce chimeric mice. The chimeric mice are then bred to yield a strain in which all the cells of the mouse contain the disrupted gene. Knockout mice are used as EXPERIMENTAL ANIMAL MODELS for diseases (DISEASE MODELS, ANIMAL) and to clarify the functions of the genes.
A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that SIROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.
Inorganic compounds that contain lithium as an integral part of the molecule.
A Wnt protein subtype that plays a role in cell-cell signaling during EMBRYONIC DEVELOPMENT and the morphogenesis of the developing NEURAL TUBE. Defects in Wnt3 protein are associated with autosomal recessive tetra-AMELIA in humans.
A family of DNA-binding proteins that are primarily expressed in T-LYMPHOCYTES. They interact with BETA CATENIN and serve as transcriptional activators and repressors in a variety of developmental processes.
A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.
Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.
An adenine nucleotide containing one phosphate group which is esterified to both the 3'- and 5'-positions of the sugar moiety. It is a second messenger and a key intracellular regulator, functioning as a mediator of activity for a number of hormones, including epinephrine, glucagon, and ACTH.
Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.
A casein kinase I isoenzyme that plays a role in intracellular signaling pathways including the WNT SIGNALING PATHWAY, the CELL CYCLE, membrane trafficking, and RNA processing. Multiple isoforms of casein kinase I alpha exist and are due to ALTERNATIVE SPLICING.
The basic cellular units of nervous tissue. Each neuron consists of a body, an axon, and dendrites. Their purpose is to receive, conduct, and transmit impulses in the NERVOUS SYSTEM.
The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.
Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)
A mitogen-activated protein kinase subfamily that is widely expressed and plays a role in regulation of MEIOSIS; MITOSIS; and post mitotic functions in differentiated cells. The extracellular signal regulated MAP kinases are regulated by a broad variety of CELL SURFACE RECEPTORS and can be activated by certain CARCINOGENS.
A Wnt protein subtype that plays a role in cell-cell signaling during EMBRYONIC DEVELOPMENT and the morphogenesis of the developing NEURAL TUBE.
Proteins and peptides that are involved in SIGNAL TRANSDUCTION within the cell. Included here are peptides and proteins that regulate the activity of TRANSCRIPTION FACTORS and cellular processes in response to signals from CELL SURFACE RECEPTORS. Intracellular signaling peptide and proteins may be part of an enzymatic signaling cascade or act through binding to and modifying the action of other signaling factors.
A phosphoprotein phosphatase subtype that is comprised of a catalytic subunit and two different regulatory subunits. At least two genes encode isoforms of the protein phosphatase catalytic subunit, while several isoforms of regulatory subunits exist due to the presence of multiple genes and the alternative splicing of their mRNAs. Protein phosphatase 2 acts on a broad variety of cellular proteins and may play a role as a regulator of intracellular signaling processes.
Intracellular signaling protein kinases that play a signaling role in the regulation of cellular energy metabolism. Their activity largely depends upon the concentration of cellular AMP which is increased under conditions of low energy or metabolic stress. AMP-activated protein kinases modify enzymes involved in LIPID METABOLISM, which in turn provide substrates needed to convert AMP into ATP.
The relationship between the dose of an administered drug and the response of the organism to the drug.
A complex signaling pathway whose name is derived from the DROSOPHILA Wg gene, which when mutated results in the wingless phenotype, and the vertebrate INT gene, which is located near integration sites of MOUSE MAMMARY TUMOR VIRUS. The signaling pathway is initiated by the binding of WNT PROTEINS to cells surface WNT RECEPTORS which interact with the AXIN SIGNALING COMPLEX and an array of second messengers that influence the actions of BETA CATENIN.
Inorganic compounds that contain bromine as an integral part of the molecule.
The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.
A gene silencing phenomenon whereby specific dsRNAs (RNA, DOUBLE-STRANDED) trigger the degradation of homologous mRNA (RNA, MESSENGER). The specific dsRNAs are processed into SMALL INTERFERING RNA (siRNA) which serves as a guide for cleavage of the homologous mRNA in the RNA-INDUCED SILENCING COMPLEX. DNA METHYLATION may also be triggered during this process.
RNA sequences that serve as templates for protein synthesis. Bacterial mRNAs are generally primary transcripts in that they do not require post-transcriptional processing. Eukaryotic mRNA is synthesized in the nucleus and must be exported to the cytoplasm for translation. Most eukaryotic mRNAs have a sequence of polyadenylic acid at the 3' end, referred to as the poly(A) tail. The function of this tail is not known for certain, but it may play a role in the export of mature mRNA from the nucleus as well as in helping stabilize some mRNA molecules by retarding their degradation in the cytoplasm.
A structurally-related group of signaling proteins that are phosphorylated by the INSULIN RECEPTOR PROTEIN-TYROSINE KINASE. The proteins share in common an N-terminal PHOSPHOLIPID-binding domain, a phosphotyrosine-binding domain that interacts with the phosphorylated INSULIN RECEPTOR, and a C-terminal TYROSINE-rich domain. Upon tyrosine phosphorylation insulin receptor substrate proteins interact with specific SH2 DOMAIN-containing proteins that are involved in insulin receptor signaling.
Transport proteins that carry specific substances in the blood or across cell membranes.
A negative regulator of beta-catenin signaling which is mutant in ADENOMATOUS POLYPOSIS COLI and GARDNER SYNDROME.
Enzymes that catalyze the transfer of glucose from a nucleoside diphosphate glucose to an acceptor molecule which is frequently another carbohydrate. EC 2.4.1.-.
Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.
The part of CENTRAL NERVOUS SYSTEM that is contained within the skull (CRANIUM). Arising from the NEURAL TUBE, the embryonic brain is comprised of three major parts including PROSENCEPHALON (the forebrain); MESENCEPHALON (the midbrain); and RHOMBENCEPHALON (the hindbrain). The developed brain consists of CEREBRUM; CEREBELLUM; and other structures in the BRAIN STEM.
A negative regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
An LDL-receptor related protein that combines with cell surface FRIZZLED RECEPTORS to form WNT PROTEIN-binding receptors. The protein plays an important role in the WNT SIGNALING PATHWAY during EMBRYONIC DEVELOPMENT and in regulation of vascular cell proliferation.
Laboratory mice that have been produced from a genetically manipulated EGG or EMBRYO, MAMMALIAN.
A large multisubunit complex that plays an important role in the degradation of most of the cytosolic and nuclear proteins in eukaryotic cells. It contains a 700-kDa catalytic sub-complex and two 700-kDa regulatory sub-complexes. The complex digests ubiquitinated proteins and protein activated via ornithine decarboxylase antizyme.
A family of serine-threonine kinases that bind to and are activated by MONOMERIC GTP-BINDING PROTEINS such as RAC GTP-BINDING PROTEINS and CDC42 GTP-BINDING PROTEIN. They are intracellular signaling kinases that play a role the regulation of cytoskeletal organization.
The process of moving proteins from one cellular compartment (including extracellular) to another by various sorting and transport mechanisms such as gated transport, protein translocation, and vesicular transport.
Linear POLYPEPTIDES that are synthesized on RIBOSOMES and may be further modified, crosslinked, cleaved, or assembled into complex proteins with several subunits. The specific sequence of AMINO ACIDS determines the shape the polypeptide will take, during PROTEIN FOLDING, and the function of the protein.
A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin.
The aggregation of soluble ANTIGENS with ANTIBODIES, alone or with antibody binding factors such as ANTI-ANTIBODIES or STAPHYLOCOCCAL PROTEIN A, into complexes large enough to fall out of solution.
Serologic tests in which a positive reaction manifested by visible CHEMICAL PRECIPITATION occurs when a soluble ANTIGEN reacts with its precipitins, i.e., ANTIBODIES that can form a precipitate.
1,4-alpha-D-Glucan-1,4-alpha-D-glucan 4-alpha-D-glucosyltransferase/dextrin 6 alpha-D-glucanohydrolase. An enzyme system having both 4-alpha-glucanotransferase (EC 2.4.1.25) and amylo-1,6-glucosidase (EC 3.2.1.33) activities. As a transferase it transfers a segment of a 1,4-alpha-D-glucan to a new 4-position in an acceptor, which may be glucose or another 1,4-alpha-D-glucan. As a glucosidase it catalyzes the endohydrolysis of 1,6-alpha-D-glucoside linkages at points of branching in chains of 1,4-linked alpha-D-glucose residues. Amylo-1,6-glucosidase activity is deficient in glycogen storage disease type III.
A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.
Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.
An enzyme of the transferase class that catalyzes the reaction 5,10-methylenetetrahydrofolate and dUMP to dihydrofolate and dTMP in the synthesis of thymidine triphosphate. (From Dorland, 27th ed) EC 2.1.1.45.
The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.
A transferase that catalyzes formation of PHOSPHOCREATINE from ATP + CREATINE. The reaction stores ATP energy as phosphocreatine. Three cytoplasmic ISOENZYMES have been identified in human tissues: the MM type from SKELETAL MUSCLE, the MB type from myocardial tissue and the BB type from nervous tissue as well as a mitochondrial isoenzyme. Macro-creatine kinase refers to creatine kinase complexed with other serum proteins.
Cell lines whose original growing procedure consisted being transferred (T) every 3 days and plated at 300,000 cells per plate (J Cell Biol 17:299-313, 1963). Lines have been developed using several different strains of mice. Tissues are usually fibroblasts derived from mouse embryos but other types and sources have been developed as well. The 3T3 lines are valuable in vitro host systems for oncogenic virus transformation studies, since 3T3 cells possess a high sensitivity to CONTACT INHIBITION.
A proto-oncogene protein and member of the Wnt family of proteins. It is expressed in the caudal MIDBRAIN and is essential for proper development of the entire mid-/hindbrain region.
Gated transport mechanisms by which proteins or RNA are moved across the NUCLEAR MEMBRANE.
Mitogen-activated protein kinase kinase kinases (MAPKKKs) are serine-threonine protein kinases that initiate protein kinase signaling cascades. They phosphorylate MITOGEN-ACTIVATED PROTEIN KINASE KINASES; (MAPKKs) which in turn phosphorylate MITOGEN-ACTIVATED PROTEIN KINASES; (MAPKs).
The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.
A CALCIUM-dependent, constitutively-expressed form of nitric oxide synthase found primarily in NERVE TISSUE.
Recombinant proteins produced by the GENETIC TRANSLATION of fused genes formed by the combination of NUCLEIC ACID REGULATORY SEQUENCES of one or more genes with the protein coding sequences of one or more genes.
Proteins obtained from the ZEBRAFISH. Many of the proteins in this species have been the subject of studies involving basic embryological development (EMBRYOLOGY).
Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.
A guanine nucleotide exchange factor that acts to restore EUKARYOTIC INITIATION FACTOR-2 to its GTP bound form.
A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.
Proteins which maintain the transcriptional quiescence of specific GENES or OPERONS. Classical repressor proteins are DNA-binding proteins that are normally bound to the OPERATOR REGION of an operon, or the ENHANCER SEQUENCES of a gene until a signal occurs that causes their release.
A broad category of carrier proteins that play a role in SIGNAL TRANSDUCTION. They generally contain several modular domains, each of which having its own binding activity, and act by forming complexes with other intracellular-signaling molecules. Signal-transducing adaptor proteins lack enzyme activity, however their activity can be modulated by other signal-transducing enzymes
Histochemical localization of immunoreactive substances using labeled antibodies as reagents.
Short sequences (generally about 10 base pairs) of DNA that are complementary to sequences of messenger RNA and allow reverse transcriptases to start copying the adjacent sequences of mRNA. Primers are used extensively in genetic and molecular biology techniques.
Protein encoded by the bcl-1 gene which plays a critical role in regulating the cell cycle. Overexpression of cyclin D1 is the result of bcl-1 rearrangement, a t(11;14) translocation, and is implicated in various neoplasms.
Phosphoprotein with protein kinase activity that functions in the G2/M phase transition of the CELL CYCLE. It is the catalytic subunit of the MATURATION-PROMOTING FACTOR and complexes with both CYCLIN A and CYCLIN B in mammalian cells. The maximal activity of cyclin-dependent kinase 1 is achieved when it is fully dephosphorylated.
Compounds that contain the radical R2C=N.OH derived from condensation of ALDEHYDES or KETONES with HYDROXYLAMINE. Members of this group are CHOLINESTERASE REACTIVATORS.
ATP:pyruvate 2-O-phosphotransferase. A phosphotransferase that catalyzes reversibly the phosphorylation of pyruvate to phosphoenolpyruvate in the presence of ATP. It has four isozymes (L, R, M1, and M2). Deficiency of the enzyme results in hemolytic anemia. EC 2.7.1.40.
The muscle tissue of the HEART. It is composed of striated, involuntary muscle cells (MYOCYTES, CARDIAC) connected to form the contractile pump to generate blood flow.
Cells grown in vitro from neoplastic tissue. If they can be established as a TUMOR CELL LINE, they can be propagated in cell culture indefinitely.
Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.
A highly conserved 76-amino acid peptide universally found in eukaryotic cells that functions as a marker for intracellular PROTEIN TRANSPORT and degradation. Ubiquitin becomes activated through a series of complicated steps and forms an isopeptide bond to lysine residues of specific proteins within the cell. These "ubiquitinated" proteins can be recognized and degraded by proteosomes or be transported to specific compartments within the cell.
A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels.
A CELL LINE derived from a PHEOCHROMOCYTOMA of the rat ADRENAL MEDULLA. PC12 cells stop dividing and undergo terminal differentiation when treated with NERVE GROWTH FACTOR, making the line a useful model system for NERVE CELL differentiation.
A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.
An abundant 43-kDa mitogen-activated protein kinase kinase subtype with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.
A dsRNA-activated cAMP-independent protein serine/threonine kinase that is induced by interferon. In the presence of dsRNA and ATP, the kinase autophosphorylates on several serine and threonine residues. The phosphorylated enzyme catalyzes the phosphorylation of the alpha subunit of EUKARYOTIC INITIATION FACTOR-2, leading to the inhibition of protein synthesis.
The protein constituents of muscle, the major ones being ACTINS and MYOSINS. More than a dozen accessory proteins exist including TROPONIN; TROPOMYOSIN; and DYSTROPHIN.
A group of enzymes that transfers a phosphate group onto an alcohol group acceptor. EC 2.7.1.
A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
A group of phenyl benzopyrans named for having structures like FLAVONES.
Endosomes containing intraluminal vesicles which are formed by the inward budding of the endosome membrane. Multivesicular bodies (MVBs) may fuse with other organelles such as LYSOSOMES or fuse back with the PLASMA MEMBRANE releasing their contents by EXOCYTOSIS. The MVB intraluminal vesicles released into the extracellular environment are known as EXOSOMES.
The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.
Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA.
High molecular weight proteins found in the MICROTUBULES of the cytoskeletal system. Under certain conditions they are required for TUBULIN assembly into the microtubules and stabilize the assembled microtubules.
Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.
Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.
A glucose transport protein found in mature MUSCLE CELLS and ADIPOCYTES. It promotes transport of glucose from the BLOOD into target TISSUES. The inactive form of the protein is localized in CYTOPLASMIC VESICLES. In response to INSULIN, it is translocated to the PLASMA MEMBRANE where it facilitates glucose uptake.
Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.
Cells in the body that store FATS, usually in the form of TRIGLYCERIDES. WHITE ADIPOCYTES are the predominant type and found mostly in the abdominal cavity and subcutaneous tissue. BROWN ADIPOCYTES are thermogenic cells that can be found in newborns of some species and hibernating mammals.
A free radical gas produced endogenously by a variety of mammalian cells, synthesized from ARGININE by NITRIC OXIDE SYNTHASE. Nitric oxide is one of the ENDOTHELIUM-DEPENDENT RELAXING FACTORS released by the vascular endothelium and mediates VASODILATION. It also inhibits platelet aggregation, induces disaggregation of aggregated platelets, and inhibits platelet adhesion to the vascular endothelium. Nitric oxide activates cytosolic GUANYLATE CYCLASE and thus elevates intracellular levels of CYCLIC GMP.
An autosomal recessive disease in which gene expression of glucose-6-phosphatase is absent, resulting in hypoglycemia due to lack of glucose production. Accumulation of glycogen in liver and kidney leads to organomegaly, particularly massive hepatomegaly. Increased concentrations of lactic acid and hyperlipidemia appear in the plasma. Clinical gout often appears in early childhood.
A viral oncoprotein originally isolated from a murine T CELL LYMPHOMA infected with the acutely transforming retrovirus AKT8. v-akt protein is the viral homologue of PROTO-ONCOGENE PROTEINS C-AKT.
Commonly observed structural components of proteins formed by simple combinations of adjacent secondary structures. A commonly observed structure may be composed of a CONSERVED SEQUENCE which can be represented by a CONSENSUS SEQUENCE.
The inactive form of GLYCOGEN PHOSPHORYLASE that is converted to the active form PHOSPHORYLASE A via phosphorylation by PHOSPHORYLASE KINASE and ATP.
Naturally occurring or experimentally induced animal diseases with pathological processes sufficiently similar to those of human diseases. They are used as study models for human diseases.
A cell surface receptor for INSULIN. It comprises a tetramer of two alpha and two beta subunits which are derived from cleavage of a single precursor protein. The receptor contains an intrinsic TYROSINE KINASE domain that is located within the beta subunit. Activation of the receptor by INSULIN results in numerous metabolic changes including increased uptake of GLUCOSE into the liver, muscle, and ADIPOSE TISSUE.
Agents that are used to treat bipolar disorders or mania associated with other affective disorders.
Proteins obtained from various species of Xenopus. Included here are proteins from the African clawed frog (XENOPUS LAEVIS). Many of these proteins have been the subject of scientific investigations in the area of MORPHOGENESIS and development.
A cyclin subtype that is specific for CYCLIN-DEPENDENT KINASE 4 and CYCLIN-DEPENDENT KINASE 6. Unlike most cyclins, cyclin D expression is not cyclical, but rather it is expressed in response to proliferative signals. Cyclin D may therefore play a role in cellular responses to mitogenic signals.
The sum of the weight of all the atoms in a molecule.
DNA sequences which are recognized (directly or indirectly) and bound by a DNA-dependent RNA polymerase during the initiation of transcription. Highly conserved sequences within the promoter include the Pribnow box in bacteria and the TATA BOX in eukaryotes.
In glycogen or amylopectin synthesis, the enzyme that catalyzes the transfer of a segment of a 1,4-alpha-glucan chain to a primary hydroxy group in a similar glucan chain. EC 2.4.1.18.
Analysis of PEPTIDES that are generated from the digestion or fragmentation of a protein or mixture of PROTEINS, by ELECTROPHORESIS; CHROMATOGRAPHY; or MASS SPECTROMETRY. The resulting peptide fingerprints are analyzed for a variety of purposes including the identification of the proteins in a sample, GENETIC POLYMORPHISMS, patterns of gene expression, and patterns diagnostic for diseases.

Alzheimer's disease: clues from flies and worms. (1/3209)

Presenilin mutations give rise to familial Alzheimer's disease and result in elevated production of amyloid beta peptide. Recent evidence that presenilins act in developmental signalling pathways may be the key to understanding how senile plaques, neurofibrillary tangles and apoptosis are all biochemically linked.  (+info)

Axin prevents Wnt-3a-induced accumulation of beta-catenin. (2/3209)

When Axin, a negative regulator of the Wnt signaling pathway, was expressed in COS cells, it coeluted with glycogen synthase kinase-3beta (GSK-3beta), beta-catenin, and adenomatous polyposis coli protein (APC) in a high molecular weight fraction on gel filtration column chromatography. In this fraction, GSK-3beta, beta-catenin, and APC were co-precipitated with Axin. Although beta-catenin was detected in the high molecular weight fraction in L cells on gel filtration column chromatography, addition of conditioned medium expressing Wnt-3a to the cells increased beta-catenin in the low molecular weight fraction. However, Wnt-3a-dependent accumulation of beta-catenin was greatly inhibited in L cells stably expressing Axin. Axin also suppressed Wnt-3a-dependent activation of Tcf-4 which binds to beta-catenin and acts as a transcription factor. These results suggest that Axin forms a complex with GSK-3beta, beta-catenin, and APC, resulting in the stimulation of the degradation of beta-catenin and that Wnt-3a induces the dissociation of beta-catenin from the Axin complex and accumulates beta-catenin.  (+info)

Allosteric regulation of even-skipped repression activity by phosphorylation. (3/3209)

The Drosophila homeodomain protein Even-skipped (Eve) is a well characterized transcriptional repressor. Here, we show that Eve's ability to function in vitro is negatively regulated by phosphorylation. DNA-binding activity was unaffected by phosphorylation, but phosphorylated Eve was unable to interact with the TATA-binding protein (TBP), a known target for repression. Unexpectedly, phosphorylation of the Eve N terminus, which is dispensable for repression and TBP binding, was necessary and sufficient to inactivate Eve. LiCl, which specifically inhibits glycogen synthase kinase-3 (GSK-3), reduced Eve phosphorylation in nuclear extract and blocked inhibition of repression. In addition, Eve was phosphorylated and inactivated by purified GSK-3 beta plus casein kinase II. Our results suggest a novel mechanism of transcriptional control involving phosphorylation-induced allosteric interference with a repressive protein-protein interaction.  (+info)

Wingless signaling leads to an asymmetric response to decapentaplegic-dependent signaling during sense organ patterning on the notum of Drosophila melanogaster. (4/3209)

Wnt and Decapentaplegic cell signaling pathways act synergistically in their contribution to macrochaete (sense organ) patterning on the notum of Drosophila melanogaster. The Wingless-signaling pathway was ectopically activated by removing Shaggy activity (the homologue of vertebrate glycogen synthase kinase 3) in mosaics. Proneural activity is asymmetric within the Shaggy-deficient clone of cells and shows a fixed "polarity" with respect to body axis, independent of the precise location of the clone. This asymmetric response indicates the existence in the epithelium of a second signal, which we suggest is Decapentaplegic. Ectopic expression of Decapentaplegic induces extra macrochaetes only in cells which also receive the Wingless signal. Activation of Hedgehog signaling generates a long-range signal which can promote macrochaete formation in the Wingless activity domain. This signal depends upon decapentaplegic function. Autonomous activation of the Wingless signal response in cells causes them to attenuate or sequester this signal. Our results suggest a novel patterning mechanism which determines sense organ positioning in Drosophila.  (+info)

Xenopus axin interacts with glycogen synthase kinase-3 beta and is expressed in the anterior midbrain. (5/3209)

Axin is encoded by the fused locus in mice and is required for normal vertebrate axis formation. It has recently been shown that axin associates with APC, beta-catenin and glycogen synthase kinase-3 (GSK-3) in a complex that appears to regulate the level of cytoplasmic beta-catenin. We have identified the Xenopus homologue of axin through its interaction with GSK-3b. Xenopus axin (Xaxin) is expressed maternally and throughout early development with a low level of ubiquitous expression. Xaxin also shows remarkably high expression in the anterior mesencephalon adjacent to the forebrain-midbrain boundary.  (+info)

Regulation of beta-catenin signaling by the B56 subunit of protein phosphatase 2A. (6/3209)

Dysregulation of Wnt-beta-catenin signaling disrupts axis formation in vertebrate embryos and underlies multiple human malignancies. The adenomatous polyposis coli (APC) protein, axin, and glycogen synthase kinase 3beta form a Wnt-regulated signaling complex that mediates the phosphorylation-dependent degradation of beta-catenin. A protein phosphatase 2A (PP2A) regulatory subunit, B56, interacted with APC in the yeast two-hybrid system. Expression of B56 reduced the abundance of beta-catenin and inhibited transcription of beta-catenin target genes in mammalian cells and Xenopus embryo explants. The B56-dependent decrease in beta-catenin was blocked by oncogenic mutations in beta-catenin or APC, and by proteasome inhibitors. B56 may direct PP2A to dephosphorylate specific components of the APC-dependent signaling complex and thereby inhibit Wnt signaling.  (+info)

Differential activation of c-Jun NH2-terminal kinase and p38 pathways during FTY720-induced apoptosis of T lymphocytes that is suppressed by the extracellular signal-regulated kinase pathway. (7/3209)

FTY720 is a novel immunosuppressive drug derived from a metabolite from Isaria sinclairii that is known to induce apoptosis of rat splenic T cells. In this study, we examined the intracellular signaling pathway triggered by FTY720. Treatment of human Jurkat T lymphocytes with FTY720-induced apoptosis characterized by DNA fragmentation. The same treatment induced activation of protein kinases such as c-Jun NH2-terminal kinase (JNK), p38/CSBP (CSAID-binding protein), and a novel 36-kDa myelin basic protein (MBP) kinase, but not extracellular signal-regulated kinase (ERK). Pretreatment of Jurkat cells with DEVD-CHO blocked FTY720-induced DNA fragmentation as well as the activation of p38/CSBP. However, DEVD-CHO treatment failed to inhibit FTY720-induced activation of JNK and the 36-kDa MBP kinase. We have also demonstrated that activation of the ERK signaling pathway completely suppressed the FTY720-induced apoptotic process including activation of caspase 3 and activation of JNK and the 36-kDa MBP kinase. Furthermore, transient expression of constitutively active mitogen-activated protein kinase/ERK kinase (MEK) protected the cells from FTY720-induced cell death. The effect of MEK was canceled by coexpression of a mitogen-activated protein kinase phosphatase, CL100. These results indicate that JNK and p38 pathways are differentially regulated during FTY720-induced apoptosis and that activation of ERK pathway alone is sufficient to cancel the FTY720-induced death signal.  (+info)

Negative regulation of axis formation and Wnt signaling in Xenopus embryos by the F-box/WD40 protein beta TrCP. (8/3209)

Screening a maternal Xenopus expression library for activities that synergize with low levels of injected beta-catenin, we have isolated a clone encoding the C-terminal end of x-beta TrCP-2, a highly conserved protein belonging to the F-box/WD40 family of ubiquitin-ligase specificity factors. We show that x-beta TrCP-2 expression reduces dorsal axis formation in Xenopus embryos. A dominant negative mutant lacking the F-box triggers the opposite effect, inducing secondary axes and activating the expression of Wnt responsive genes in ectodermal explants. In light of the existence of beta TrCP transcripts associated with the vegetal cortex, we propose that beta TrCP plays a fundamental role in the establishment of the dorsal determinants during cortical rotation in Xenopus.  (+info)

Title: The Possible Involvement of Glycogen Synthase Kinase-3 (GSK-3) in Diabetes, Cancer and Central Nervous System Diseases. VOLUME: 17 ISSUE: 22. Author(s):Amar S., Belmaker R.H. and Agam G.. Affiliation:Beer-Sheba Mental Health Center PO Box 4600, Beer-Sheba ISRAEL.. Keywords:Glycogen synthase kinase 3-β, diabetes, cancer, CNS, bipolar disorder, schizophrenia, Wnt signaling, postmortem brain, lithium, inflammation. Abstract: Glycogen synthase kinase (GSK-3) is a key enzyme in multiple cell processes. Since many pharmacological compounds that have effects on common metabolic pathways may have uses in many different diseases, we review here the possible involvement of glycogen synthase kinase 3 in diabetes, cancer and CNS diseases. Moreover, diabetes has recently been strongly linked to CNS diseases such as schizophrenia and bipolar illness. GSK-3 is both directly and indirectly inhibited by lithium, a key compound for treatment of bipolar disorder. Several antipsychotic drugs also affect the ...
Active Aβ immunotherapy in Alzheimers disease (AD) induces removal of Aβ and phosphorylated tau (ptau). Glycogen Synthase Kinase (GSK)-3β is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA dependent protein kinase (pPKR). Using a post-mortem cohort of immunised AD cases, we investigated the effect of Abeta immunisation on GSK-3β expression and pPKR ...
A-kinase anchoring proteins (AKAPs) include a family of scaffolding proteins that target protein kinase A (PKA) and other signaling proteins to cellular compartments and thereby confine the activities of the associated proteins to distinct regions within cells. AKAPs bind PKA directly. The interaction is mediated by the dimerization and docking domain of regulatory subunits of PKA and the PKA-binding domain of AKAPs. Analysis of the interactions between the dimerization and docking domain and various PKA-binding domains yielded a generalized motif allowing the identification of AKAPs. Our bioinformatics and peptide array screening approaches based on this signature motif identified GSKIP (glycogen synthase kinase 3beta interaction protein) as an AKAP. GSKIP directly interacts with PKA and GSK3beta (glycogen synthase kinase 3beta). It is widely expressed and facilitates phosphorylation and thus inactivation of GSK3beta by PKA. GSKIP contains the evolutionarily conserved domain of unknown function ...
Glycogen synthase kinase-3 (GSK-3) exclusive position in modulating the function of the diverse group of protein in conjunction with it is association with a multitude of human disorders offers attracted significant focus on the proteins both being a therapeutic focus on and as a way to understand the molecular basis of the disorders. mobile stimulants. This paper will concentrate on the different methods to control GSK-3 activity (phosphorylation, proteins complex development, truncation, subcellular localization, etc.), the primary signalling pathways involved with its control, and its own pathological deregulation. 1. Launch Glycogen synthase kinase-3 (GSK-3) is really a CMGC serine/threonine proteins kinase initially referred to as among the kinases that phosphorylates and inhibits glycogen synthase [1]. It really is now widely recognized though that GSK-3 has an important function in various important physiological processes, such as for example development, cell routine, or apoptosis [2]. ...
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Glycogen Synthase Kinase 3 (GSK-‑3) is a serine/threonine protein kinase and one of several protein kinases, which phosphorylate glycogen synthase. It is also called Factor A (F A ) for its ability to activate the MgATP-dependent form of the protein phosphatase PP1 called F C (1-4)
The WNT signalling pathway controls many developmental processes and plays a key role in maintenance of intestine renewal and homeostasis. Glycogen Synthase Kinase 3 (GSK3) is an important component of the WNT pathway and is involved in regulating β-catenin stability and expression of WNT target genes. The mechanisms underpinning GSK3 regulation in this context are not completely understood, with some evidence suggesting this occurs through inhibitory N-terminal serine phosphorylation in a similar way to GSK3 inactivation in insulin signaling. To investigate this in a physiologically relevant context, we have analysed the intestinal phenotype of GSK3 knockin mice in which N-terminal serines 21/9 of GSK3α/β have been mutated to non-phosphorylatable alanine residues. We show that these knockin mutations have very little effect on overall intestinal integrity, cell lineage commitment, β-catenin localization or WNT target gene expression although a small increase in apoptosis at villi tips is ...
The transcription factor NF-E2-related factor 2 (Nrf2) is a master regulator of a genetic program, termed the phase 2 response, that controls redox homeostasis and participates in multiple aspects of physiology and pathology. Nrf2 protein stability is regulated by two E3 ubiquitin ligase adaptors, Keap1 and ß-TrCP, the latter of which was only recently reported. Here, two-dimensional (2D) gel electrophoresis and site-directed mutagenesis allowed us to identify two serines of Nrf2 that are phosphorylated by glycogen synthase kinase 3ß (GSK-3ß) in the sequence DSGISL. Nuclear magnetic resonance studies defined key residues of this phosphosequence involved in docking to the WD40 propeller of ß-TrCP, through electrostatic and hydrophobic interactions. We also identified three arginine residues of ß-TrCP that participate in Nrf2 docking. Intraperitoneal injection of the GSK-3 inhibitor SB216763 led to increased Nrf2 and heme oxygenase-1 levels in liver and hippocampus. Moreover, mice with ...
Recent Research Presentations (Personally presented):. Natural compounds isolated from diverse plants and their usefulness for combating fatal diseases like human oral cancer. BELMSBR, Mar 29-30, 2017 at NOU, Baripada, India. (Invited Talk). Application of Synthetic/ Natural Compounds for Combating Oral Cancer: Role of an Enzyme Glycogen Synthase Kinase 3 beta. ICFCS, Mar 16-18, 2017 at CUJ, Ranchi, India. (Invited Lecture) Awakening GSK3beta (glycogen synthase kinase 3beta), the resting conqueror, to fight against human oral epithelial cancer. World Congress on Cancer Research & Therapy on Nov 21-23, 2016 at Miami, FL, USA. (Invited Talk). Aggressiveness of human oral cancer and the role of glycogen synthase kinase 3 isoforms α/β signaling. 12th Asian Clinical Oncology Society Conference (ACOS- 2016), April 8-10, New Delhi, India. Aggressiveness of tobacco mediated human oral cancer and the role of glycogen synthase kinase 3 isoforms α/β signaling. International Conference on Environmental ...
Dive into the research topics of Staphylococcus aureus induces microglial inflammation via a glycogen synthase kinase 3β-regulated pathway. Together they form a unique fingerprint. ...
Exacerbated hippocampal activity has been associated to critical modifications of the intracellular signaling pathways. We have investigated rapid hippocampal adaptive responses induced by maximal electroshock seizure (MES). Here, we demonstrate that abnormal and exacerbated hippocampal activity induced by MES triggers specific and temporally distinct patterns of phosphorylation of extracellular signal-related kinase (ERK), mammalian target of rapamycin complex (mTORC) and Akt/glycogen synthase kinase-3 (Akt/GSK-3) pathways in the mouse hippocampus. While the ERK pathway is transiently activated, the mTORC1 cascade follows a rapid inhibition followed by a transient activation. This rebound of mTORC1 activity leads to the selective phosphorylation of p70S6K, which is accompanied by an enhanced phosphorylation of the ribosomal subunit S6. In contrast, the Akt/GSK-3 pathway is weakly altered. Finally, MES triggers a rapid upregulation of several plasticity-associated genes as a consequence exacerbated
Phosphatidylinositol-3 kinase (PI3-K) and protein kinase B (Akt) activation not only stimulate NO production, but they also inhibit glycogen synthase kinase-3β (GSK3β) (8). Similarly, activation of canonical Wnt signaling inactivates GSK3β (9). Wnts are secreted glycoproteins known to regulate hematopoiesis and stem cell function (9). In the unstimulated cell, GSK3β phosphorylates and accelerates degradation of HIF-1α and β-catenin (9,10). Inhibition of GSK3β leads to cytosolic accumulation and nuclear translocation of these transcription factors in a manner that increases EPC survival, proliferation, differentiation, mobilization, and adhesion (11-13). EPCs pretreated with GSK inhibitors or EPCs that are genetically modified to overexpress VEGF or inactive GSK3β enhance vasculogenesis, augment reendothelialization, and reduce neointimal formation (11-13).. Diabetes is associated with reduced endothelial NO bioavailability and PI3-K/Akt activity, and EPCs are defective and reduced in ...
The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. The therapy of certain diseases, such as acute myeloid leukemia (AML), may require α-isoform specific targeting. The scorpion shaped GSK-3 inhibitors developed by our group achieved the highest GSK-3α selectivity reported so far but suffered from insufficient aqueous solubility. This work presents the solubility-driven optimization of our isoform-selective inhibitors using a scorpion shaped lead. Among 15 novel compounds, compound 27 showed high activity against GSK-3α/β with the highest GSK-3α selectivity reported to date. Compound 27 was profiled for bioavailability and toxicity in a zebrafish embryo phenotype assay. Selective GSK-3α targeting in AML cell lines was achieved with compound 27, resulting in a strong differentiation phenotype and colony formation impairment, confirming the potential of GSK-3α inhibition in AML therapy. ...
Background Inhibition of glycogen synthase kinase-3 (GSK-3) improves the efficiency of embryonic stem (ES) cell derivation from various strains of mice and rats, as well as dramatically promotes ES cell self-renewal potential. β-catenin has been reported to be involved in the maintenance of self-renewal of ES cells through TCF dependent and independent pathway. But the intrinsic difference between ES cell lines from different species and strains has not been characterized. Here, we dissect the mechanism of GSK-3 inhibition by CHIR99021 in mouse ES cells from refractory mouse strains. Methodology/Principal Findings We found that CHIR99021, a GSK-3 specific inhibitor, promotes self-renewal of ES cells from recalcitrant C57BL/6 (B6) and BALB/c mouse strains through stabilization of β-catenin and c-Myc protein levels. Stabilized β-catenin promoted ES self-renewal through two mechanisms. First, β-catenin translocated into the nucleus to maintain stem cell pluripotency in a lymphoid-enhancing factor/T
Abstract Background Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine (Ser/Thr) kinase comprising two isoforms, GSK-3 and GSK-3. procedures. Nevertheless, the specificity of these antibodies in immunocytochemistry offers not really been resolved in any fine detail. ResultsTaking benefit of gene silencing technology, we analyzed the specificity of many in a commercial sense obtainable anti-phosphorylated GSK-3 antibodies. We display that antibodies elevated to peptides made up of the phosphorylated Ser21/9 epitope crossreact with mysterious antigens that are extremely indicated by mitotic cells and that primarily localise to spindle poles. In addition, two antibodies elevated to peptides made up of the phosphorylated Tyr279/216 epitope recognise an mysterious proteins at focal connections, and a third antibody recognises a proteins discovered in Ki-67-positive cell nuclei. While the phosphorylated Ser9/21 GSK-3 antibodies also recognise additional protein whose ...
The phosphorylation of Amyloid Precursor Protein (APP) at Thr668 plays a key role in APP metabolism that is highly relevant to AD. The c-Jun-N-terminal kinase (JNK), glycogen synthase kinase-3β (GSK-3β) and cyclin-dependent kinase 5 (Cdk5) can all be responsible for this phosphorylation. These kinases are activated by excitotoxic stimuli fundamental hallmarks of AD. The exposure of cortical neurons to a high dose of NMDA (100 μM) for 30-45 led to an increase of P-APP Thr668. During NMDA stimulation APP hyperphosphorylation has to be assigned to GSK-3β activity, since addition of L803-mts, a substrate competitive inhibitor of GSK-3β reduced APP phosphorylation induced by NMDA. On the contrary, inhibition of JNK and Cdk5 with D-JNKI1 and Roscovitine respectively did not prevent NMDA-induced P-APP increase. These data show a tight connection, in excitotoxic conditions, between APP metabolism and the GSK-3β signaling pathway.
TY - JOUR. T1 - Glycogen synthase kinase-3β inhibition enhances myelination in preterm newborns with intraventricular hemorrhage, but not recombinant Wnt3A. AU - Dohare, Preeti. AU - Cheng, Bokun. AU - Ahmed, Ehsan. AU - Yadala, Vivek. AU - Singla, Pranav. AU - Thomas, Sunisha. AU - Kayton, Robert. AU - Ungvari, Zoltan. AU - Ballabh, Praveen. PY - 2018/10. Y1 - 2018/10. N2 - Intraventricular hemorrhage (IVH) in preterm infants results in reduced proliferation and maturation of oligodendrocyte progenitor cells (OPCs), and survivors exhibit reduced myelination and neurological deficits. Wnt signaling regulates OPC maturation and myelination in a context dependent manner. Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3β inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. These ...
Neural stem cells (NSCs) hold great potential for the treatment of neurodegenerative diseases. However, programmed cell death (PCD) provoked by the harsh conditions evident in the diseased brain greatly undermines the potential of NSCs. Currently, the mechanisms of PCD that effect NSCs remain largely unknown. We have previously reported that hippocampal neural stem (HCN) cells derived from the adult rat brain undergo autopahgic cell death (ACD) following insulin withdrawal without hallmarks of apoptosis despite their normal apoptotic capabilities. In this study, we demonstrate that glycogen synthase kinase 3β (GSK-3β) induces ACD in insulin-deprived HCN cells. Both pharmacological and genetic inactivation of GSK-3β significantly decreased ACD, while activation of GSK-3β increased autophagic flux and caused more cell death without inducing apoptosis following insulin withdrawal. In contrast, knockdown of GSK-3α barely affected ACD, lending further support to the critical role of GSK-3β.
The graphic displays domains and Protease cut sites on the protein sequence. Drag your mouse right/left over the graphic. Use the selection boxes on the right to select which annotations to view simultaneously. Combine annotation with multiple checkmarks.. ...
ABSTRACTGlycogen synthase kinase-3 (GSK3) is a serine/threonine protein kinase firstly identified as a regulator of glycogen synthesis. Recently, it has been proved to be a key regulator of the immune reaction. In the present study, a GSK3 homolog gene (designated as EsGSK3) was cloned from Chinese
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IL-33 is a cytokine belonging to the IL-1 family and plays a critical role in the pathogenesis of pulmonary inflammatory diseases (7, 32). IL-33 induces IL-6 and IL-8 release in lung epithelial cells and macrophages, and increases lung endothelial permeability (7, 9). The biological effects of IL-33 are through interactions with its receptor ST2L. Therefore, understanding the regulation of cell surface expression of ST2L is important for limiting lung inflammation and injury. Ligand-induced receptor internalization and downregulation are crucial steps to control the magnitude and duration of extracellular signals in eukaryotes. Our previous studies demonstrated that ST2L is ubiquitinated and degraded in response to IL-33 in a GSK3β activation-dependent manner (5). In this study, we extend our understanding of ST2L downregulation by demonstrating a role for GSK3β in the regulation of ST2L receptor internalization. The current study indicates that FAK-activated GSK3β modulates ST2L ...
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Purpose: Evasion from chemotherapy-induced apoptosis due to p53 loss strongly contributes to drug resistance. Identification of specific targets for the treatment of drug-resistant p53-null tumors would therefore increase the effectiveness of cancer therapy.. Experimental Design: By using a kinase-directed short hairpin RNA library and HCT116p53KO drug-resistant colon carcinoma cells, glycogen synthase kinase 3 beta (GSK3B) was identified as a target whose silencing bypasses drug resistance due to loss of p53. p53-null colon cancer cell lines with different sets of mutations were used to validate the role of GSK3B in sustaining resistance and to characterize cell death mechanisms triggered by chemotherapy when GSK3B is silenced. In vivo xenograft studies were conducted to confirm resensitization of drug-resistant cells to chemotherapy upon GSK3 inhibition. Colon cancer samples from a cohort of 50 chemotherapy-treated stage II patients were analyzed for active GSK3B expression.. Results: ...
Glycogen synthase kinase 3 has evolutionarily conserved roles in cell signaling and metabolism and is a recognized drug target in neurological pathologies, most prominently bipolar disorder. More recently it has been suggested that GSK3 may be a target for the treatment of trypanosomatid parasite infections, e.g. w
rIPC [remote IPC (ischaemic preconditioning)] has been shown to invoke potent myocardial protection in animal studies and recent clinical trials. Although the important role of PI3K (phosphoinositide 3-kinase)/Akt activation in the cardioprotection afforded by local IPC is well described, our understanding of the intracellular signalling of rIPC remains incomplete. We therefore examined the hypothesis that the myocardial protection afforded by rIPC is mediated via the PI3K/Akt/GSK3β (glycogen synthase kinase 3β) signalling pathway, activation of which is associated with nuclear accumulation of β-catenin. rIPC was induced in mice using four cycles of 5 min of ischaemia and 5 min of reperfusion of the hindlimb using a torniquet. This led to reduced infarct size (19±4% in rIPC compared with 39±7% in sham; P,0.05), improved functional recovery and reduced apoptosis after global I/R (ischaemia/reperfusion) injury using a Langendorff-perfused mouse heart model. These effects were reversed by ...
Kirschenbaum F, Hsu SC, Cordell B, McCarthy JV. Substitution of a glycogen synthase kinase-3beta phosphorylation site in presenilin 1 separates presenilin function from beta-catenin signaling ...
GSK3B / GSK3 Beta (C-Terminus) antibody | P49841 | Glycogen synthase kinase-3 beta, GSK-3 beta, Serine/threonine-protein kinase GSK3B, Gsk 3beta, GSK3 beta, GSK3beta
Development of protein kinase inhibitors is a focus of many drug discovery programs. A major problem, however, is the limited specificity of the commonly used adenosine triphosphate-competitive inhibitors and the weak inhibition of the more selective substrate-competitive inhibitors. Glycogen synthase kinase-3 (GSK-3) is a promising drug target for treating neurodegenerative disorders, including Alzheimers disease (AD), but most GSK-3 inhibitors have not reached the clinic. We describe a new type of GSK-3 inhibitor, L807mts, that acts through a substrate-to-inhibitor conversion mechanism that occurs within the catalytic site of the enzyme. We determined that L807mts was a potent and highly selective GSK-3 inhibitor with reasonable pharmacological and safety properties when tested in rodents. Treatment with L807mts enhanced the clearance of β-amyloid loads, reduced inflammation, enhanced autophagic flux, and improved cognitive and social skills in the 5XFAD AD mouse model. This new modality of ...
1o6l_A mol:protein length:337 RAC-BETA SERINE/THREONINE PROTEIN KINASE KVTMNDFDYLKLLGKGTFGKVILVREKATGRYYAMKILRKEVIIAKDEVAHTVTESRVL QNTRHPFLTALKYAFQTHDRLCFVMEYANGGELFFHLSRERVFTEERARFYGAEIVSAL EYLHSRDVVYRDIKLENLMLDKDGHIKITDFGLCKEGISDGATMKTFCGTPEYLAPEVL EDNDYGRAVDWWGLGVVMYEMMCGRLPFYNQDHERLFELILMEEIRFPRTLSPEAKSLL AGLLKKDPKQRLGGGPSDAKEVMEHRFFLSINWQDVVQKKLLPPFKPQVTSEVDTRYFD DEFTAQSITITPPDRYDSLGLLELDQREEQEMFEDFDYIADW >1o6l_C mol:protein length:10 GLYCOGEN SYNTHASE KINASE-3 BETA GRPRTTSFAE >1o6l_C mol:protein length:10 GLYCOGEN SYNTHASE KINASE-3 BETA GRPRTTSFAE ...
國璽幹細胞與安南醫院心臟內科部長李聰明教授共同合作,由李教授以冠狀動脈左前降枝結紮手術(ligation of the left anterior descending artery, LAD)模擬心肌梗塞後的心律不整模式,結合國璽幹細胞的「醫藥級脂肪幹細胞製劑生產技術平台」製造的幹細胞,成功證實調控PI3K/Akt/GSK-3β訊息傳遞路徑,有助於降低發生心肌梗塞後所造成的心律不整。研究成果刊登於Journal of Molecular and Cellular ...
Glycogen synthase kinase-3 (GSK-3) is a widely expressed and highly conserved serine/threonine protein kinase encoded by two genes that generate two related proteins: GSK-3α and GSK-3β. Mice lacking a functional GSK-3α gene were engineered in our laboratory; they are viable and display insulin sensitivity. In this study, we have characterized brain functions of GSK-3α KO mice by using a well-established battery of behavioral tests together with neurochemical and neuroanatomical analysis. Similar to the previously described behaviours of GSK-3β+/-mice, GSK-3α mutants display decreased exploratory activity, decreased immobility time and reduced aggressive behavior. However, genetic inactivation of the GSK-3α gene was associated with: decreased locomotion and impaired motor coordination, increased grooming activity, loss of social motivation and novelty; enhanced sensorimotor gating and impaired associated memory and coordination. GSK-3α KO mice exhibited a deficit in fear conditioning, however
Phosphatidylinositol-3 kinase (PI3-K) and protein kinase B (Akt) activation not only stimulate NO production, but they also inhibit glycogen synthase kinase-3β (GSK3β) (8). Similarly, activation of canonical Wnt signaling inactivates GSK3β (9). Wnts are secreted glycoproteins known to regulate hematopoiesis and stem cell function (9). In the unstimulated cell, GSK3β phosphorylates and accelerates degradation of HIF-1α and β-catenin (9,10). Inhibition of GSK3β leads to cytosolic accumulation and nuclear translocation of these transcription factors in a manner that increases EPC survival, proliferation, differentiation, mobilization, and adhesion (11-13). EPCs pretreated with GSK inhibitors or EPCs that are genetically modified to overexpress VEGF or inactive GSK3β enhance vasculogenesis, augment reendothelialization, and reduce neointimal formation (11-13).. Diabetes is associated with reduced endothelial NO bioavailability and PI3-K/Akt activity, and EPCs are defective and reduced in ...
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Structure of the asymmetric unit of the human lamin A/C fragment. Structural basis for lamin assembly at the molecular level, Nature Communications (2019). Conversion of cell-survival activity of Akt into apoptotic death of cancer cells by two mutations on the BIM BH3 domain, Cell. Death. Dis. (2015). Development of Akt-activated GSK3β inhibitory peptide, Biochem. Biophys. Res. Commun. (2013). Role of CK1 in GSK3beta-mediated phosphorylation and degradation of Snail, Oncogene (2010). The role of the Ser/Thr cluster in the phosphorylation of PPPSP motif in Wnt coreceptors, Biochem. Biophys. Res. Commun. (2009). ...
Alzheimers disease (AD) is one of the most common neurological disorders with vast reaching worldwide prevalence. Research attempts to decipher whats happening to the human mind have shown that...
Glycogen synthase kinase 3 beta inhibitor Chir025 reduces neuronal death resulting from oxygen-glucose deprivation, glutamate excitotoxicity, and cerebral isc
Several kinases implicated in multiple signaling pathways elicit conflicting responses depending on the cellular context. One such kinase is glycogen synthase kinase 3 (GSK3), a cytoplasmic serine-threonine kinase that is involved in insulin signaling and metabolic regulation, as well as in Wnt signaling and the specification of cell fates during embryonic development (3). GSK3 appears in two highly homologous and ubiquitously expressed forms, GSK3α and GSK3β (4). The insulin and Wnt signaling pathways differentially regulate GSK3α/β resulting in distinct downstream events (5), but how they accomplish this is not clear. The recent report of the crystal structure of GSK3β by Dajani and colleagues in Cell (6), together with a biochemical study of GSK3_ by Frame et al. in Molecular Cell (7), reveal how GSK3 selectively regulates different downstream targets according to which signaling pathway is activated.. GSK3 is unusual among kinases in that its normal activity in the cytoplasm is blocked ...
Glycogen synthase kinase 3 (GSK-3) in its active state complexes with APC and AXIN to suppress phosphorylation of β-catenin, which then gets degraded via the proteasome. GSK-3 becomes inactivated through the PI3K/AKT pathway when the cell receives signals like growth factors, cytokines, or insulin. WNT signaling can also inactivate GSK-3 through Dsh. Inactivation of GSK-3 leads to gene expression, cell survival, and cell proliferation.. Click on the poster below to view the interactive version.. ...
Dysregulation of glycogen synthase kinase (GSK-3β) is implicated in the pathophysiology of many diseases, including type-2 diabetes, stroke, Alzheimers, and others. A multistage virtual screening strategy designed so as to overcome known caveats arising from the considerable flexibility of GSK-3β yielded, from among
As the major downstream target of mammalian target of rapamycin complex 1 (mTORC1), S6K phosphorylates multiple downstream substrates including S6, eIF4B, and GSK3 (glycogen synthase kinase 3) to regulate various key cellular processes including protein synthesis, cell size, cell proliferation (18-21), and cell migration (22). However, the biochemical and biological functions of different S6K family proteins including S6K1 (which consists of the p70S6K1 and p85S6K1 isoforms) and S6K2 (also known as p56S6K2) are relatively undefined (23). In keeping with a possible oncogenic role for S6K kinases, bioinformatics analysis indicated that both S6K1 and S6K2 were amplified in multiple human cancers, especially in breast cancers (fig. S2, A and B). The amplification of S6K1 and S6K2 appeared to be mutually exclusive in breast cancers (fig. S2C), suggesting possibly redundant functions of S6K1 and S6K2. Structurally, p85S6K1 shared a high degree of homology in amino acid sequence with p56S6K2, except ...
The AlphaLISA® SureFire® Ultra™ p-GSK-3β (Ser9) assay kit is an immunoassay for quantitative detection of endogenous GSK-3β (phosphorylated at Ser9) in cellular lysates.
Of the discovery of GSK3 (glycogen synthase kinase 3) inhibitors there has been no end. I first came across it as a target it about 1997, and even then, once I
Rac)-BRD0705 (Rac)-BRD0705 is a less active racemate of BRD0705. BRD0705 is a potent, paralog selective and orally active GSK3α inhibitor with an IC50 of 66 nM and a Kd of 4.8 μM. BRD0705 displays increased selectivity for GSK3α (8-fold) versus GSK3β (IC50 of 515 nM). BRD0705 can be used for acute myeloid leukemia (AML).. ...
Crosstide is a peptide analog of glycogen synthase kinase α/β fusion protein sequence which is a substrate for Akt. - Mechanism of Action & Protocol.
Abstract Background Glycogen synthase kinase-3 (GSK-3) is a ubiquitously expressed serine/threonine (Ser/Thr) kinase comprising two isoforms, GSK-3 and GSK-3. procedures. Nevertheless, the specificity of these antibodies in immunocytochemistry offers not really been resolved in any fine detail. ResultsTaking benefit of gene silencing technology, we analyzed the specificity of many in a commercial sense obtainable anti-phosphorylated GSK-3 antibodies. We display that antibodies elevated to peptides made up of the phosphorylated Ser21/9 epitope crossreact with mysterious antigens that are extremely indicated by mitotic cells and that primarily localise to spindle poles. In addition, two antibodies elevated to peptides made up of the phosphorylated Tyr279/216 epitope recognise an mysterious proteins at focal connections, and a third antibody recognises a proteins discovered in Ki-67-positive cell nuclei. While the phosphorylated Ser9/21 GSK-3 antibodies also recognise additional protein whose ...
Enhancing β-cell proliferation is a major goal for type 1 and type 2 diabetes research. Unraveling the network of β-cell intracellular signaling pathways that promote β-cell replication can provide the tools to address this important task. In a previous Perspectives in Diabetes article, we discussed what was known regarding several important intracellular signaling pathways in rodent β-cells, including the insulin receptor substrate/phosphatidylinositol-3 kinase/Akt (IRS-PI3K-Akt) pathways, glycogen synthase kinase-3 (GSK3) and mammalian target of rapamycin (mTOR) S6 kinase pathways, protein kinase Cζ (PKCζ) pathways, and their downstream cell-cycle molecular targets, and contrasted that ample knowledge to the small amount of complementary data on human β-cell intracellular signaling pathways ...
In the prior funding period, we demonstrated that conditional elimination of the Glycogen Synthase Kinase-3s (GSK-3s), a and ?, in the embryonic nervous system...
Glycogen synthase kinase-3 (GSK-3) is ubiquitously expressed throughout the brain and involved in vital molecular pathways such as cell survival and synaptic reorganization and has emerged as a potential drug target for brain diseases. A causal role for GSK-3, in particular the brain-enriched GSK-3β isoform, has been demonstrated in neurodegenerative diseases such as Alzheimers and Huntingtons, and in psychiatric diseases. ...
"A-kinase anchoring protein AKAP220 binds to glycogen synthase kinase-3beta (GSK-3beta ) and mediates protein kinase A-dependent ... May 2002). "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta ... Glycogen synthase kinase 3 beta, also known as GSK3B, is an enzyme that in humans is encoded by the GSK3B gene. In mice, the ... "Entrez Gene: GSK3B glycogen synthase kinase 3 beta". Iwahashi K, Nishizawa D, Narita S, Numajiri M, Murayama O, Yoshihara E, et ...
Glycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene. Glycogen synthase kinase 3-alpha EC ... "Entrez Gene: GSK3A glycogen synthase kinase 3 alpha". Gerdin AK (2010). "The Sanger Mouse Genetics Programme: High throughput ... Glycogen synthase kinase 3 GRCh38: Ensembl release 89: ENSG00000105723 - Ensembl, May 2017 GRCm38: Ensembl release 89: ... Ali A, Hoeflich KP, Woodgett JR (Aug 2001). "Glycogen synthase kinase-3: properties, functions, and regulation". Chemical ...
Ali A, Hoeflich KP, Woodgett JR (August 2001). "Glycogen synthase kinase-3: properties, functions, and regulation". Chemical ... Protein kinase C beta type is an enzyme that in humans is encoded by the PRKCB gene. Protein kinase C (PKC) is a family of ... "Protein kinase C-associated kinase (PKK), a novel membrane-associated, ankyrin repeat-containing protein kinase". The Journal ... PRKCB1 has been shown to interact with RIPK4, beta adrenergic receptor kinase, PDLIM5 and GNB2L1. Protein kinase C GRCh38: ...
Ali A, Hoeflich KP, Woodgett JR (2002). "Glycogen synthase kinase-3: properties, functions, and regulation". Chem. Rev. 101 (8 ... Protein kinase C gamma type is an enzyme that in humans is encoded by the PRKCG gene. Protein kinase C (PKC) is a family of ... specifically require this kinase. Knockout studies in mice also suggest that this kinase may be involved in neuropathic pain ... This protein kinase is expressed solely in the brain and spinal cord and its localization is restricted to neurons. It has been ...
"Regulation of glycogen synthase kinase-3 during bipolar mania treatment". Bipolar Disord. 12 (7): 741-52. doi:10.1111/j.1399- ... Yildiz A, Guleryuz S, Ankerst DP, Ongür D, Renshaw PF (2008). "Protein kinase C inhibition in the treatment of mania: a double- ... 2 (3): 136-146. ISSN 1723-8617. PMC 1525098 . PMID 16946919.. *^ Nusslock, Robin; Young, Christina B.; Damme, Katherine S. F. ( ... 65 (3): 255-63. doi:10.1001/archgenpsychiatry.2007.43. PMID 18316672.. *^ Brietzke E, Stertz L, Fernandes BS, Kauer-Sant'anna M ...
Martín CP, Vázquez J, Avila J, Moreno FJ (2002). "P24, a glycogen synthase kinase 3 (GSK 3) inhibitor". Biochim. Biophys. Acta ... identification of sites targeted by different kinases". J. Biol. Chem. 282 (40): 29531-9. doi:10.1074/jbc.M703466200. hdl:2437/ ... 2006). "Interaction of TPPP/p25 protein with glyceraldehyde-3-phosphate dehydrogenase and their co-localization in Lewy bodies ...
"Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3 by Tideglusib" (PDF). The Journal of Biological Chemistry. ... ATP-competitive glycogen synthase kinase 3 (GSK-3) inhibitor.. Potential applications[edit]. Tideglusib is under investigation ... "Evidence for Irreversible Inhibition of Glycogen Synthase Kinase-3 by Tideglusib". Journal of Biological Chemistry. 287 (2): ... As of 2017 it was undergoing Phase IIa[2] and IIb clinical trials.[3][4][5][6] The first trial to be published (in English) was ...
"Nuclear export of NF-ATc enhanced by glycogen synthase kinase-3". Science. 275 (5308): 1930-4. doi:10.1126/science.275.5308. ... mitogen-activated protein kinase p38 binding. • FK506 binding. • transcriptional activator activity, RNA polymerase II distal ... Porter CM, Havens MA, Clipstone NA (Feb 2000). "Identification of amino acid residues and protein kinases involved in the ... Transcriptional activity of NFATc1 is enhanced by the Pim-1 kinase". Journal of Immunology. 168 (4): 1524-7. doi:10.4049/ ...
Gardner, Phyllis (1997-03-28). "Nuclear Export of NF-ATc Enhanced by Glycogen Synthase Kinase-3". Science. 275 (5308): 1930- ...
Glycogen Synthase Kinase 3 Beta (GSK3B) GSK3B is a protein kinase that regulates transcription factors and microtubules. As ... "GSK3B - Glycogen synthase kinase-3 beta - Homo sapiens (Human) - GSK3B gene & protein". www.uniprot.org. Retrieved 2017-04-23. ... Serine/Threonine-Protein Kinase PAK 1 (PAK 1), and DNA Replication Factor Cdt1 (CDT1). KIAA1211L is associated with depression ... protein kinases assay, two hybrid, and confocal microscopy experiments. KIAA1211L protein is also predicted to interact with ...
Activation of the Wnt pathway inhibits glycogen synthase kinase 3 beta (GSK3B). When the Wnt pathway is not active, GSK3 beta ... Second generation inhibitors are able to bind to the ATP-binding motif on the kinase domain of the mTOR core protein itself and ... Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis PB, Thomas G (May 2002). "Regulation of an activated S6 kinase 1 variant ... De P, Miskimins K, Dey N, Leyland-Jones B (Aug 2013). "Promise of rapalogues versus mTOR kinase inhibitors in subset specific ...
Kawabe, Yoshinori; Morio, Takahiro; Tanaka, Yoshimasa; Schaap, Pauline (2018-05-09). "Glycogen synthase kinase 3 promotes ... 138 (3): 387-396. doi:10.1242/dev.048934. ISSN 0950-1991. PMC 3014629. PMID 21205784. "Pauline Schaap - AcademiaNet". www. ...
Glycogen synthase kinase-3β, NF-κB signaling, and tumorigenesis of human osteosarcoma. „J Natl Cancer Inst". 104 (10), s. 749- ... The cyclin-dependent kinase inhibitor SCH 727965 (dinacliclib) induces the apoptosis of osteosarcoma cells. „Mol Cancer Ther". ... Clinical and biological significance of PIM1 kinase in osteosarcoma. „J Orthop Res", Dec 2015. DOI: 10.1002/jor.23134. PMID: ... Transforming growth factor-beta as a key molecule triggering the expression of versican isoforms v0 and v1, hyaluronan synthase ...
... in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB". J. Biol. Chem ... stimulates glycogen synthase, and glucose 6 phosphate may inhibit the phosphorylation of glycogen synthase by cyclic AMP- ... The role of glucose 6-phosphate in glycogen synthase: High blood glucose concentration causes an increase in intracellular ... Phosphorylation of src tyrosine kinase (pronounced "sarc") by C-terminal Src kinase (Csk) induces a conformational change in ...
2007). "Glycogen synthase kinase-3 phosphorylates CdGAP at a consensus ERK 1 regulatory site". J. Biol. Chem. 282 (6): 3624-31 ... 2010). "A human MAP kinase interactome". Nat. Methods. 7 (10): 801-5. doi:10.1038/nmeth.1506. PMC 2967489. PMID 20936779. Jenna ...
"Mitochondrial hexokinase II promotes neuronal survival and acts downstream of glycogen synthase kinase-3". The Journal of ... As an isoform of hexokinase and a member of the sugar kinase family, HK2 catalyzes the rate-limiting and first obligatory step ... Activation of Akt kinase maintains HK2-VDAC coupling, which subsequently prevents cytochrome c release and apoptosis, though ... In a similar mechanism, the pro-apoptotic creatine kinase binds and opens VDAC in the absence of HK2. An alternative model ...
Glycogen synthase kinase 3 (GSK3) seems to be over-expressed in most cancer cells. GSK3 is involved in promoter activation ... Viral proteins like viral thymidine kinase can be used for specific targeting of a drug. By introducing a prodrug only ... kinase/Akt, heat shock protein 90, and mammalian target of rapamycin in transformed NK cells". Journal of Immunology. 174 (9): ... 10 (3): 281-7. doi:10.1016/S1074-7613(00)80028-X. PMID 10204484. Takahashi K, Tanabe K, Ohnuki M, Narita M, Ichisaka T, Tomoda ...
"Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B". Nature. 378 (6559): 785-9. doi:10.1038/ ...
Cross DA, Alessi DR, Cohen P, Andjelkovich M, Hemmings BA (December 1995). "Inhibition of glycogen synthase kinase-3 by insulin ... Discovery of the key signaling kinase PKB (Akt) and demonstration of its central role in cancer cell signaling. First use of ... Saitoh M, Pullen N, Brennan P, Cantrell D, Dennis PB, Thomas G (May 2002). "Regulation of an activated S6 kinase 1 variant ... mediated by protein kinase B.". Nature. 378 (6559): 785-789. doi:10.1038/378785a0. PMID 8524413. Ludin B, Doll T, Meili R, ...
"Presenilin 1 regulates beta-catenin-mediated transcription in a glycogen synthase kinase-3-independent fashion". The Journal of ... 37 (3): 254-77. doi:10.1210/er.2015-1146. PMID 27159876. Slattery ML, Folsom AR, Wolff R, Herrick J, Caan BJ, Potter JD (April ... 277 (3): 1884-91. doi:10.1074/jbc.M110248200. PMID 11711551. Graham TA, Ferkey DM, Mao F, Kimelman D, Xu W (December 2001). " ... 62 (3): 706-8. doi:10.2337/db12-1418. PMC 3581232. PMID 23431017. Duggirala R, Blangero J, Almasy L, Dyer TD, Williams KL, ...
... in insulin-induced glycogen synthase kinase 3 inactivation. Characterization of dominant-negative mutant of PKB". J. Biol. Chem ... It was found that an enzyme, named phosphorylase kinase and Mg-ATP were required to phosphorylate glycogen phosphorylase by ... Cyclin-dependent kinases (CDKs) are serine-threonine kinases which regulate progression through the eukaryotic cell cycle. CDKs ... Most phosphorylation is carried out by a single superfamily of protein kinases that share a conserved kinase domain. Protein ...
Ali A, Hoeflich KP, Woodgett JR (Aug 2001). "Glycogen synthase kinase-3: properties, functions, and regulation". Chemical ... Protein kinase C alpha (PKCα) is an enzyme that in humans is encoded by the PRKCA gene. Protein kinase C (PKC) is a family of ... Protein kinase C-alpha (PKC-α) is a specific member of the protein kinase family. These enzymes are characterized by their ... PKC-α is unique in its mode of regulation compared to other kinases within this family. In general, the protein kinase family ...
"Entrez Gene: PRKD3 protein kinase D3". Ali A, Hoeflich KP, Woodgett JR (2002). "Glycogen synthase kinase-3: properties, ... 2002). "Human serum and glucocorticoid-inducible kinase-like kinase (SGKL) phosphorylates glycogen syntheses kinase 3 beta (GSK ... 2000). "Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A". Proc. Natl. Acad. Sci. U.S.A. 97 ( ... 2002). "Convergence of Multiple Signaling Cascades at Glycogen Synthase Kinase 3: Edg Receptor-Mediated Phosphorylation and ...
Ali A, Hoeflich KP, Woodgett JR (2002). "Glycogen synthase kinase-3: properties, functions, and regulation". Chem. Rev. 101 (8 ... Protein kinase C delta type (or PKC-δ) is an enzyme that in humans is encoded by the PRKCD gene. Protein kinase C (PKC) is a ... "Entrez Gene: PRKCD protein kinase C, delta". Welman A, Griffiths JR, Whetton AD, Dive C (December 2007). "Protein kinase C ... Protein kinase C delta is also regulated by phosphorylation on various serine/threonine (e.g. T50, T141, S304, T451, T505, S506 ...
"Temporal correlation of the memory deficit with Alzheimer-like lesions induced by activation of glycogen synthase kinase-3". ... 117 (3): 659-71. doi:10.1172/JCI29562. PMC 1797603. PMID 17318264.. *^ a b Hahnen E, Eyüpoglu IY, Brichta L, Haastert K, ... M (y) 2; H (ni) 3 M (y) 9; H (ny) D (y) 11 R (y) 17; H (ny) MC 23, 24; M (y) 25; H (v) 26, 27, 28, 29 ... 19 (3): 895-907. doi:10.3233/JAD-2010-1284. PMID 20157245.. *^ Byun CJ, Seo J, Jo SA, Park YJ, Klug M, Rehli M, Park MH, Jo I ( ...
"The low density lipoprotein receptor-related protein 6 interacts with glycogen synthase kinase 3 and attenuates activity". J. ... 248 (3): 879-88. doi:10.1006/bbrc.1998.9061. PMID 9704021. "Entrez Gene: LRP6 low density lipoprotein receptor-related protein ...
The Akt and ERK pathways converge to alter glycogen synthase kinase-3 beta (GSK-3β) activity. Specifically, Akt and ERK ... generates reactive oxygen species and activates reperfusion injury salvage kinases". PLOS ONE. 9 (1): e87205. Bibcode:2014PLoSO ... and activation of the reperfusion injury salvage kinase pathway (RISK). The mitochondrial accumulation of acylcarnitines ( ... 3 (6): 186-200. doi:10.4330/wjc.v3.i6.186. PMC 3139040. PMID 21772945. Martel C, Huynh L, Garnier A, Ventura-Clapier R, Brenner ...
Glycogen synthase. *Debranching enzyme. *Branching enzyme. *1,3-Beta-glucan synthase. *Ceramide glucosyltransferase ... doi:10.1016/S1367-5931(02)00390-3. PMID 12470740.. *^ Nilsson I, Kelleher DJ, Miao Y, Shao Y, Kreibich G, Gilmore R, von Heijne ... The sugar Glc3Man9GlcNAc2 (where Glc=Glucose, Man=Mannose, and GlcNAc=N-acetylglucosamine) is attached to an asparagine (Asn) ... They are labelled "Type I" if the defective gene is for an enzyme involved in the assembly or transfer of the Glc3Man9GlcNAc2- ...
Glucose ⇄ glycogen. Glycogenesis. *GSD type 0 (glycogen synthase deficiency). *GSD type IV (Andersen's disease, branching ... GSD type IX (phosphorylase kinase deficiency). Lysosomal (LSD):. *GSD type II (Pompe's disease, glucosidase deficiency) ... 8 (3): 157. doi:10.3390/nu8030157. PMC 4808885. PMID 26978392.. *^ a b c d e f Storhaug CL, Fosse SK, Fadnes LT (October 2017 ... GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency). *GSD type V (McArdle's disease, myophosphorylase ...
2004). "Regulation of type 1 protein phosphatase/inhibitor-2 complex by glycogen synthase kinase-3beta in intact cells". J. ... positive regulation of protein kinase activity. • regulation of cyclin-dependent protein serine/threonine kinase activity. • ... CDK5R2, NCK5AI, P39, p39nck5ai, cyclin-dependent kinase 5, regulatory subunit 2 (p39), cyclin dependent kinase 5 regulatory ... Cyclin-dependent kinase 5 activator 2 is an enzyme that in humans is encoded by the CDK5R2 gene.[5][6] ...
... kinase activates glycogen phosphorylase in the same manner mentioned previously. ... Lactose synthase. *B-N-acetylglucosaminyl-glycopeptide b-1,4-galactosyltransferase. *Glycoprotein-N-acetylgalactosamine 3-beta- ... Glycogen phosphorylase is one of the phosphorylase enzymes (EC 2.4.1.1). Glycogen phosphorylase catalyzes the rate-limiting ... α-1,4 glycogen chain)n + Pi ⇌ (α-1,4 glycogen chain)n-1 + α-D-glucose-1-phosphate.[2] ...
positive regulation of glycogen (starch) synthase activity. Sources:Amigo / QuickGO. Orthologs. Species. Human. Mouse. ... protein serine/threonine kinase activator activity. • receptor ligand activity. Cellular component. • extracellular region. • ... positive regulation of glycogen biosynthetic process. • positive regulation of transcription from RNA polymerase II promoter. • ... positive regulation of protein kinase B signaling. • regulation of transcription, DNA-templated. • ossification. • platelet ...
Casein kinase *1. *2. *eIF-2 kinase *EIF2AK3. *Glycogen synthase kinase *GSK1 ...
"Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin". Molecular and ... 4 (3): 222-31. doi:10.1038/ncb758. PMID 11836526.. *^ Vodermaier HC, Gieffers C, Maurer-Stroh S, Eisenhaber F, Peters JM ( ... 270 (3): 903-9. doi:10.1006/bbrc.2000.2471. PMID 10772923.. *^ Geng L, Burrow CR, Li HP, Wilson PD (December 2000). " ... 83 (1-2): 82-3. doi:10.1159/000015134. PMID 9925936.. *^ Semb H, Christofori G (December 1998). "The tumor-suppressor function ...
Casein kinase *1. *2. *eIF-2 kinase *EIF2AK3. *Glycogen synthase kinase *GSK1 ... 1omw: Crystal Structure of the complex between G Protein-Coupled Receptor Kinase 2 and Heterotrimeric G Protein beta 1 and ... Buhl AM, Osawa S, Johnson GL (1995). "Mitogen-activated protein kinase activation requires two signal inputs from the human ... 2bcj: Crystal Structure of G Protein-Coupled Receptor Kinase 2 in Complex with Galpha-q and Gbetagamma Subunits ...
PLP aids in the synthesis of hemoglobin, by serving as a coenzyme for the enzyme ALA synthase.[6] It also binds to two sites on ... PLP is a required coenzyme of glycogen phosphorylase, the enzyme necessary for glycogenolysis to occur.[4] PLP can catalyze ... Absorbed pyridoxamine is converted to PMP by pyridoxal kinase, which is further converted to PLP by pyridoxamine-phosphate ... PLP is a coenzyme needed for the proper function of the enzymes cystathionine synthase and cystathionase. These enzymes ...
ALAS1: aminolevulinate, delta-, synthase 1. *APEH: encoding enzyme Acylamino-acid-releasing enzyme ... ULK4: UNC-51 like kinase 4. *VGLL3: vestigial-like family member 3 ... Glycogen storage disease. *Hailey-Hailey disease. *Harderoporphyrinuria. *Heart block, progressive/nonprogressive. *Hereditary ... 3. q 29. 11175. 11700. 192,600,001. 198,295,559 gneg. References[edit]. *^ "Human Genome Assembly GRCh38 - Genome Reference ...
"Pyruvate dehydrogenase kinase-4 contributes to the recirculation of gluconeogenic precursors during postexercise glycogen ... Cysteine synthase, for example, catalyzes the formation of acetic acids and cysteine from O3-acetyl-L-serine and hydrogen ... A prominent kinase is cyclin-dependent kinase (or CDK), which comprises a sub-family of protein kinases. As their name implies ... "Biochemical characterization of the human cyclin-dependent protein kinase activating kinase. Identification of p35 as a novel ...
This in turn leads to increased cAMP-dependent protein kinase or PKA (protein kinase A) activity, ultimately promoting ... Metabolic disorders: glycogen storage disease, Gaucher disease, thyroid diseases. *Others: pulmonary tumoral thrombotic ... In normal conditions, the vascular endothelial nitric oxide synthase produces nitric oxide from L-arginine in the presence of ... The cGMP then activates cGMP-dependent kinase or PKG (protein kinase G). Activated PKG promotes vasorelaxation (via a reduction ...
stimulates AC, raises cAMP, stimulates beta catenin and Glycogen synthase kinase 3 ... and Extracellular signal-regulated kinases (ERK), p38 mitogen-activated protein kinases (p38 Mpk), and cAMP response element- ... cell signaling agents and for activating protein kinase C (PKC) secondary messengers; ... EP3. PGE2,PGF2α,PGI2,PGD2=TXA2[10]. inhibitory. Gi & G12 subunit. inhibits AC, decreases cAMP, stimulates PLC & IP3, raises Ca ...
Glucose ⇄ glycogen. Glycogenesis. *GSD type 0 (glycogen synthase deficiency). *GSD type IV (Andersen's disease, branching ... GSD type IX (phosphorylase kinase deficiency). Lysosomal (LSD):. *GSD type II (Pompe's disease, glucosidase deficiency) ... GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency). *GSD type V (McArdle's disease, myophosphorylase ... Type 3. 29842 230350. GALE. 1p36-p35. UDP galactose epimerase. galactose epimerase deficiency, UDP-Galactose-4-epimerase ...
Casein kinase *1. *2. *eIF-2 kinase *EIF2AK3. *Glycogen synthase kinase *GSK1 ... Glucagon - Stimulates glycogen breakdown in the liver. *hCG - Promotes cellular differentiation, and is potentially involved in ... cAMP can then act as a second messenger that goes on to interact with and activate protein kinase A (PKA). PKA can ... for their discovery of how glycogen is broken down to glucose and resynthesized in the body, for use as a store and source of ...
... and glycogen synthase kinase 3 responses. These data suggest that upregulation of talin-1 in cardiac hypertrophy may be ... 2h7e: Solution structure of the talin F3 domain in complex with a chimeric beta3 integrin-PIP kinase peptide- minimized average ... Chen HC, Appeddu PA, Parsons JT, Hildebrand JD, Schaller MD, Guan JL (Jul 1995). "Interaction of focal adhesion kinase with ... 2h7d: Solution structure of the talin F3 domain in complex with a chimeric beta3 integrin-PIP kinase peptide ...
phosphorylate glycogen synthase (inhibiting it)[10]. *stimulate glycolysis *phosphorylate phosphofructokinase 2 (stimulating it ... out of 540 different protein kinase genes that make up for human kinome, only one other protein kinase, Casein kinase 2, is ... phosphorylate glycogen phosphorylase via phosphorylase kinase (activating it)[10]. *phosphorylate Acetyl-CoA carboxylase ( ... "cAMP-dependent protein kinase" redirects here. It is not to be confused with AMP-activated protein kinase or cyclin-dependent ...
"Interaction of glycogen synthase kinase 3beta with the DF3/MUC1 carcinoma-associated antigen and beta-catenin". Mol. Cell. Biol ... Commun. 270 (3): 903-9. PMID 10772923. doi:10.1006/bbrc.2000.2471.. *↑ Geng L, Burrow CR, Li HP, Wilson PD (December 2000). " ... 14,0 14,1 14,2 14,3 Kinch MS, Clark GJ, Der CJ, Burridge K (July 1995). "Tyrosine phosphorylation regulates the adhesions of ... 15,0 15,1 15,2 15,3 Hazan RB, Norton L (April 1998). "The epidermal growth factor receptor modulates the interaction of E- ...
... and glucose 6 phosphate may inhibit the phosphorylation of glycogen synthase by cyclic AMP-stimulated protein kinase.[7] ... Villar-Palasí, C.; Guinovart, J. J. (1 June 1997). "The role of glucose 6-phosphate in the control of glycogen synthase". The ... The role of glucose 6-phosphate in glycogen synthase: High blood glucose concentration causes an increase in intracellular ... Allosteric activation by glucose 6 phosphate, which acts as an effector, stimulates glycogen synthase, ...
... nuclear located protein kinase C and cyclic AMP-dependent protein kinase". Frontiers in Bioscience. 13 (13): 1206-26. doi: ... In comparison to glycogen which would contribute only half of the energy per its pure mass, triglyceride carbons are all bonded ... Chirala SS, Wakil SJ (November 2004). "Structure and function of animal fatty acid synthase". Lipids. 39 (11): 1045-53. doi: ... Nowicki M, Müller F, Frentzen M (April 2005). "Cardiolipin synthase of Arabidopsis thaliana". FEBS Letters. 579 (10): 2161-5. ...
Glucose ⇄ glycogen. Glycogenesis. *GSD type 0 (glycogen synthase deficiency). *GSD type IV (Andersen's disease, branching ... GSD type IX (phosphorylase kinase deficiency). Lysosomal (LSD):. *GSD type II (Pompe's disease, glucosidase deficiency) ... GSD type VI (Hers' disease, liver glycogen phosphorylase deficiency). *GSD type V (McArdle's disease, myophosphorylase ... β-D-fructofuranosyl-(2→1)-α-D-glucopyranoside; β-(2S,3S,4S,5R)-fructofuranosyl-α-(1R,2R,3S,4S,5R)-glucopyranoside; α-(1R,2R,3S, ...
After the liver has replenished its glycogen stores (which amount to only about 100 g of glycogen when full) much of the rest ... In animals, as well as some fungi such as yeast, these same reactions occur on fatty acid synthase I (FASI), a large dimeric ... The glycerol released by lipase action is phosphorylated by glycerol kinase in the liver (the only tissue in which this ... For example, 1 g of glycogen can bind approximately 2 g of water, which translates to 1.33 kcal/g (4 kcal/3 g). This means that ...
Casein kinase *1. *2. *eIF-2 kinase *EIF2AK3. *Glycogen synthase kinase *GSK1 ... In humans, cAMP works by activating protein kinase A (PKA, cAMP-dependent protein kinase), one of the first few kinases ... an enzyme called protein kinase A (PKA).[12]. The PKA enzyme is also known as cAMP-dependent enzyme because it gets activated ... enzymes that convert glycogen into glucose. *enzymes that promote muscle contraction in the heart leading to an increase in ...
Casein kinase *1. *2. *eIF-2 kinase *EIF2AK3. *Glycogen synthase kinase *GSK1 ... Cyclins, when bound with the dependent kinases, such as the p34/cdc2/cdk1 protein, form the maturation-promoting factor. MPFs ... Nurse won the 2001 Nobel Prize in Physiology or Medicine for their discovery of cyclin and cyclin-dependent kinase.[17] ... doi:10.1016/S0969-2126(01)00259-3. PMID 8591034.. *^ Davies TG, Tunnah P, Meijer L, Marko D, Eisenbrand G, Endicott JA, Noble ...
Gould, Todd; Picchini, Alyssa; Einat, Haim; Manji, Husseini (2006-11-01). "Targeting Glycogen Synthase Kinase-3 in the CNS: ... glycogen synthase kinase 3β). Inhibition of pAp-phosphatase by lithium leads to increased levels of pAp (3′-5′ phosphoadenosine ... 3C. 6H. 5O. 7) is also used in conventional pharmacological treatments. Lithium orotate (C. 5H. 3LiN. 2O. 4), has been ... 77 (3): 219-224. doi:10.1038/ki.2009.433. PMID 19940841.. *^ Shepard, T.H.; Brent, R.L.; Friedman, J.M.; Jones, K.L.; Miller, R ...
"Reciprocal targeting of Hath1 and beta-catenin by Wnt glycogen synthase kinase 3beta in human colon cancer". Gastroenterology. ... doi:10.1007/s00335-001-2101-3. PMC 2262845. PMID 11889557.. الوسيط ,CitationClass=. تم تجاهله (مساعدة). ...
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... is a serine/threonine protein kinase and one of several protein kinases, which phosphorylate glycogen synthase. It is also ... is a serine/threonine protein kinase and one of several protein kinases, which phosphorylate glycogen synthase. It is also ... Protein Kinases Information. Applications: Protein Phosphatases & Kinases. * Properties and Usage Unit Definition. One unit is ... 1X NEBuffer™ for Protein Kinases (PK) 50 mM Tris-HCl 10 mM MgCl2 0.1 mM EDTA 2 mM DTT 0.01% Brij 35 (pH 7.5 @ 25°C) ...
Expression and function of glycogen synthase kinase-3 in human hair follicles.. Yamauchi K1, Kurosaka A. ... and inhibition of glycogen synthase kinase-3 (GSK-3) increases beta-catenin concentration in the cytoplasm. To examine the ... A GSK-3 inhibitor, BIO, promoted the growth of human outer root sheath cells, which could be cultured for up to four passages. ... Contrary to GSK-3beta, GSK-3 alpha was widely expressed throughout the follicles when immunostained with a specific antibody, ...
Glycogen synthase kinase-3 beta. A, B. 414. Homo sapiens. Mutation(s): 0 Gene Names: GSK3B. EC: 2.7.1.37 (PDB Primary Data), ... Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as ... Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as ... crystal structure of Glycogen synthase kinase 3 in complexed with inhibitor. *DOI: 10.2210/pdb1Q5K/pdb ...
... in the same manner as glycogen synthase. In Wnt signaling, GSK3B forms a multimeric complex with APC, AXIN1 and CTNNB1/beta- ... by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), EIF2B, CTNNB1/beta-catenin, APC, AXIN1, DPYSL2/CRMP2, JUN ... contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen ... Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt ...
Contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen ... by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. Requires primed ... Regulates glycogen metabolism in liver, but not in muscle. May also mediate the development of insulin resistance by regulating ... Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt ...
4). Two proline-directed kinases, glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase-5 are thought to be key ... Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo. Wendy Noble, ... Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo ... Inhibition of glycogen synthase kinase-3 by lithium correlates with reduced tauopathy and degeneration in vivo ...
... is a multifunctional serine/threonine kinase. We showed that the expression of GSK3 beta was drastically down-regulated in ... Glycogen synthase kinase 30 (GSK3 beta) is a multifunctional serine/threonine kinase. We showed that the expression of GSK3 ... The role of glycogen synthase kinase 3 beta in the transformation of epidermal cells.. ... Overexpression of a kinase-deficient (K85R) GSK3 beta, in contrast, potentiated anchorage-independent growth and drastically ...
AKT or protein kinase B (PKB), and glycogen synthase kinase (GSK)-3β (the phosphatidylinositol 3-kinase/Akt/GSK-3β pathway) (1 ... Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE, Birnbaum MJ: The role of glycogen synthase kinase 3beta in insulin- ... Nikoulina SE, Ciaraldi TP, Mudaliar S, Carter L, Johnson K, Henry RR: Inhibition of glycogen synthase kinase 3 improves insulin ... Eldar-Finkelman H, Krebs EG: Phosphorylation of insulin receptor substrate 1 by glycogen synthase kinase 3 impairs insulin ...
... glycogen synthase kinase 3 beta), Authors: Dinesh Kumar Thotala, Eugenia M Yazlovitskaya. Published in: Atlas Genet Cytogenet ... GSK3B Kinase-like_dom_sf Prot_kinase_dom Protein_kinase_ATP_BS Ser/Thr_kinase_AS ... Glycogen synthase kinase-3 beta; a new target in pancreatic cancer?. Garcea G, Manson MM, Neal CP, Pattenden CJ, Sutton CD, ... GSK3B (glycogen synthase kinase 3 beta). Written. 2010-04. Dinesh Kumar Thotala, Eugenia M Yazlovitskaya. ...
We show that homozygous deletion of glycogen synthase kinase (GSK) 3β (GSK3β−/−) bypasses senescence induced by mutant RasV12 ... Homozygous deletion of glycogen synthase kinase 3β bypasses senescence allowing Ras transformation of primary murine ... Homozygous deletion of glycogen synthase kinase 3β bypasses senescence allowing Ras transformation of primary murine ... Homozygous deletion of glycogen synthase kinase 3β bypasses senescence allowing Ras transformation of primary murine ...
In addition, DHM increased glycogen synthase kinase-3 beta phosphorylation in a dose- and time-dependent manner, which may be ... Additionally, mice were treated with either 5 or 10 mg/kg DHM for a total of 13 d (3 d before the start of MPTP, during MPTP ... The present study demonstrated that DHM is a potent neuroprotective agent for DA neurons by modulating the Akt/GSK-3β pathway, ... Male C57BL/6 mice were intraperitoneally injected with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 d to induce PD ...
Protein target information for Glycogen synthase kinase-3 beta (human). Find diseases associated with this biological target ...
Glycogen Synthase Kinase 3 (GSK-3) and Its Inhibitors: Drug Discovery and Development. Ana Martinez (Editor), Ana Castro ( ... Structures of Glycogen Synthase Kinase 3. 5. Kinase-Kinase and Site-Site Interactions in the Phosphorylation of Tau by GSK-3. ... 7. Glycogen Synthase Kinase-3: A Target for Novel Mood Disorder Treatments. 8. GSK3 and Stem Cells. 9. Glycogen Synthase Kinase ... Glycogen Synthase Kinase 3 (GSK-3) and Its Inhibitors: Drug Discovery and Development. ...
1997) Regulation of protein kinase B and glycogen synthase kinase-3 by insulin and beta-adrenergic agonists in rat epididymal ... 1996) Regulation of mitochondrial pyruvate dehydrogenase activity by tau protein kinase I/glycogen synthase kinase 3beta in ... OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase. Proc Natl ... 1992) Glycogen synthase kinase-3 and the Alzheimer-like state of microtubule-associated protein tau. FEBS Lett 314:315-321. ...
Glycogen Synthase Kinase-3β Haploinsufficiency Mimics the Behavioral and Molecular Effects of Lithium. W. Timothy OBrien, ... De Sarno P, Li X, Jope RS (2002) Regulation of Akt and glycogen synthase kinase-3beta phosphorylation by sodium valproate and ... Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, Woodgett JR (2000) Requirement for glycogen synthase kinase-3beta in cell ... Song L, De Sarno P, Jope RS (2002) Central role of glycogen synthase kinase-3beta in endoplasmic reticulum stress-induced ...
Possible role of mitogen-activated protein kinase (MAPK), glycogen synthase kinase-3 (GSK-3) and p70 S6K phosphorylation. J Mol ... Aberrant nuclear accumulation of glycogen synthase kinase-3beta in human pancreatic cancer: Association with kinase activity ... Tang QL, Xie XB, Wang J, Chen Q, Han AJ, Zou CY, Yin JQ, Liu DW, Liang Y, Zhao ZQ, et al: Glycogen synthase kinase-3β, NF-κB ... Mishra R: Glycogen synthase kinase 3 beta: Can it be a target for oral cancer. Mol Cancer. 9:1442010. View Article : Google ...
Glycogen synthase kinase-3β (GSK3β) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt ... is a physiologic inhibitor of c-RAF kinase and nuclear factor κB signaling that represses tumor invasion and metastasis. ... Raf kinase inhibitor protein RKIP enhances signaling by glycogen synthase kinase-3β Cancer Res. 2011 Feb 15;71(4):1334-43. doi ... Glycogen synthase kinase-3β (GSK3β) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt ...
... is a serine-threonine kinase that exists as two isoforms, alpha and beta, encoded by separate genes. Phosphorylation targets ... Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase that exists as two isoforms, alpha and beta, encoded by ... Isolation and chromosomal mapping of human glycogen synthase kinase-3 alpha and -3 beta encoding genes Genome. 1998 Oct;41(5): ... Two clones, 220 and 285 kb in size, containing the complete GSK-3 alpha coding sequence, and two clones, 365 and 285 kb in size ...
... and animal behavioral studies showing that serotonin regulates the activation states of brain glycogen synthase kinase-3 (GSK3 ... and animal behavioral studies showing that serotonin regulates the activation states of brain glycogen synthase kinase-3 (GSK3 ... Jope, R. S., and Johnson, G. V. W. (2004). The glamour and gloom of glycogen synthase kinase-3. Trends Biochem. Sci. 29, 95-102 ... Glycogen synthase kinase-3 is an intermediate modulator of serotonin neurotransmission. Abigail M. Polter and Xiaohua Li* ...
Glycogen synthase kinase-3 beta in complex with 3-indolyl-4-arylmaleimide inhibitor. ...
... a serine/threonine-protein kinase has been implicated in a number of diseases including st ... Over activity of Glycogen synthase kinase-3β (GSK-3β), ... Over activity of Glycogen synthase kinase-3β (GSK-3β), a serine ... Insight into glycogen synthase kinase-3β inhibitory activity of phyto-constituents from Melissa officinalis: in silico studies ... Iwaloye, O., Elekofehinti, O.O., Oluwarotimi, E.A. et al. Insight into glycogen synthase kinase-3β inhibitory activity of phyto ...
Tolnay, M., Juang, Y.-T., and Tsokos, G. C. (2002) Protein kinase A enhances, whereas glycogen synthase kinase-3β inhibits, the ... Here we report the O-GlcNAc perturbations in response to inhibition of glycogen synthase kinase-3 (GSK-3), a pivotal kinase ... Gould, T. D., and Manji, H. K. (2005) Glycogen synthase kinase-3: a putative molecular target for lithium mimetic drugs. ... Zhang, F., Phiel, C. J., Spece, L., Gurvich, N., and Klein, P. S. (2003) Inhibitory phosphorylation of glycogen synthase kinase ...
Glycogen synthase from rabbit skeletal muscle. Amino acid sequence at the sites phosphorylated by glycogen synthase kinase-3, ... Role of glycogen synthase kinase-3 in cell fate and epithelial-mesenchymal transitions. Cells Tissues Organs 2007;185:73-84pmid ... Glycogen synthase kinase (GSK) 3β is a serine/threonine kinase originally identified as an enzyme that phosphorylates and ... Glycogen Synthase Kinase-3β Inhibition Ameliorates Cardiac Parasympathetic Dysfunction in Type 1 Diabetic Akita Mice. ...
Glycogen synthase kinase-3 (GSK-3) regulates various intracellular signaling pathways; its role in TGF-β(1) -induced ... The effect of GSK-3 inhibition on α-sm-actin expression was similar in fibroblasts from individuals with and without COPD. ... Neither smad, NF-κB, nor ERK1/2 were involved in the inhibitory actions of GSK-3 inhibition by SB126763 on myofibroblast ... Moreover, silencing of GSK-3 by siRNA or pharmacological inhibition by CT/CHIR99021 fully inhibited the TGF-β(1) -induced ...
To further validate our top hits, we conducted in vitro kinase assays with recombinant proteins and identified the splicing ... based on direct kinase assays or genetic and pharmacological manipulation of GSK-3, in diverse cell types. Many more have been ... ubiquitously expressed kinase that acts as a critical regulator of many signaling pathways. These pathways, when dysregulated, ... As a result, there remains an unclear picture of the complete GSK-3 phosphoproteome. We have therefore used a large-scale mass ...
Assaying the glycogen synthase kinase-3 (GSK3) activity in sperm is of great importance because it is closely implicated in ... Rapid Detection of Glycogen Synthase Kinase-3 Activity in Mouse Sperm Using Fluorescent Gel Shift Electrophoresis. Hoseok Choi ... Choi, H.; Choi, B.; Seo, J.T.; Lee, K.J.; Gye, M.C.; Kim, Y.-P. Rapid Detection of Glycogen Synthase Kinase-3 Activity in Mouse ... Assaying the glycogen synthase kinase-3 (GSK3) activity in sperm is of great importance because it is closely implicated in ...
Binding Sites; Glycogen Synthase Kinase 3/antagonists & inhibitors/chemistry; Hydantoins/chemical synthesis/chemistry; ... SAR and 3D-QSAR studies on thiadiazolidinone derivatives: exploration of structural requirements for glycogen synthase kinase 3 ... SAR and 3D-QSAR studies on thiadiazolidinone derivatives: exploration of structural requirements for glycogen synthase kinase 3 ... The 2,4-disubstituted thiadiazolidinones (TDZD) are described as the first ATP-noncompetitive GSK-3 inhibitors. Following an ...
Safety Study of a Glycogen Synthase Kinase 3 (GSK3) Inhibitor in Patients With Alzheimer´s Disease. The safety and scientific ... No history of treatment with Memantine within 3 months prior to baseline evaluation. Patients with a stable and well tolerated ... Enrolment in another investigational study or intake of investigational drug within the previous 3 months. ...
  • Glycogen synthase kinase 3 (GSK3) is a serine/threonine kinase that has been implicated in pathological conditions such as diabetes and Alzheimer's disease. (rcsb.org)
  • 100 microM) or 26 other kinases demonstrating high specificity for GSK3. (rcsb.org)
  • AR-A014418 is the first compound of a family of specific inhibitors of GSK3 that does not significantly inhibit closely related kinases such as cdk2 or cdk5. (rcsb.org)
  • Glycogen synthase kinase 30 (GSK3 beta) is a multifunctional serine/threonine kinase. (cdc.gov)
  • Overexpression of a kinase-deficient (K85R) GSK3 beta, in contrast, potentiated anchorage-independent growth and drastically enhanced in vivo turnorigenicity. (cdc.gov)
  • We show that homozygous deletion of glycogen synthase kinase (GSK) 3β (GSK3β −/− ) bypasses senescence induced by mutant Ras V12 allowing primary mouse embryo fibroblasts (MEFs) as well as immortalized MEFs to exhibit a transformed phenotype in vitro and in vivo . (pnas.org)
  • The p53 pathway induces plasminogen activator inhibitor-1 (PAI-1) with subsequent down-regulation of the phosphatidylinositol-3-kinase (PI3K)/Akt/PTEN/GSK3β-cyclin D1 pathway ( 16 ). (pnas.org)
  • 3. Role of GSK3/Shaggy in neuronal cell biology. (wiley.com)
  • Glycogen synthase kinase-3β (GSK3β) activity is negatively regulated by several signal transduction cascades that protect neurons against apoptosis, including the phosphatidylinositol-3 kinase (PI-3 kinase) pathway. (jneurosci.org)
  • Consequently, we evaluated the role of GSK3β in apoptosis in cultured cortical neurons induced by trophic factor withdrawal or by PI-3 kinase inhibition. (jneurosci.org)
  • We conclude that inhibition of GSK3β is one of the mechanisms by which PI-3 kinase activation protects neurons from programmed cell death. (jneurosci.org)
  • Because the PI-3 kinase-Akt pathway is neural-protective and negatively regulates GSK3β activity, GSK3β may be an important downstream proapoptotic target that contributes to apoptosis in neurons. (jneurosci.org)
  • Consistent with this hypothesis, Pap and Cooper (1998) demonstrated that GSK3β activity is required for apoptosis induced by inhibition of PI-3 kinase in Rat1 fibroblasts and neuronal-like PC12 cells. (jneurosci.org)
  • Jope RS, Yuskaitis CJ and Beurel E: Glycogen synthase kinase-3 (GSK3): Inflammation, diseases, and therapeutics. (spandidos-publications.com)
  • Glycogen synthase kinase-3β (GSK3β) suppresses tumor progression by downregulating multiple oncogenic pathways including Wnt signaling and cyclin D1 activation. (nih.gov)
  • Depletion of RKIP augments oxidative stress-mediated activation of the p38 mitogen activated protein kinase, which, in turn, inactivates GSK3β by phosphorylating it at the inhibitory T390 residue. (nih.gov)
  • This review will provide evidence from biochemical, pharmacological, and animal behavioral studies showing that serotonin regulates the activation states of brain glycogen synthase kinase-3 (GSK3) via type 1 and type 2 serotonin receptors. (frontiersin.org)
  • From our analysis, we selected 65 phosphoproteins that exhibited significantly reduced phosphorylation in Gsk3 DKO ESCs as high-confidence candidate substrates of GSK-3. (upenn.edu)
  • Assaying the glycogen synthase kinase-3 (GSK3) activity in sperm is of great importance because it is closely implicated in sperm motility and male infertility. (mdpi.com)
  • Here we investigated the kinome selectivity of a library of pyrrolo[3,4- c ]pyrazol inhibitors that were developed against T. brucei GSK3 but that also interact with the human orthologue and other protein kinases. (rsc.org)
  • The fibroblast growth factor 14·voltage-gated sodium channel complex is a new target of glycogen synthase kinase 3 (GSK3). (sigmaaldrich.com)
  • To gain insights into the dynamic regulation of this protein/protein interaction complex, we employed the split luciferase complementation assay to screen a small molecule library of kinase inhibitors against the FGF14·Nav1.6 channel complex and identified inhibitors of GSK3 as hits. (sigmaaldrich.com)
  • The context of these phosphoamino acids implicates glycogen synthase kinase 3 (GSK3), whose activity is known to be repressed in response to insulin, as a potential kinase for phosphorylation of T222 and T226. (asm.org)
  • Treatment of 3T3-L1 adipocytes with the phosphatidylinositol 3-kinase inhibitor wortmannin results in phosphorylation of C/EBPα, whereas treatment with the GSK3 inhibitor lithium results in dephosphorylation of C/EBPα. (asm.org)
  • In this study, we demonstrate that glycogen synthase kinase 3β (GSK3β) regulates ST2L internalization and IL-33 signaling. (jimmunol.org)
  • Glycogen synthase kinase 3β (GSK3β) is a key signaling Ser/Thr kinase that has diverse biological effects. (jimmunol.org)
  • The serine/threonine kinase, glycogen synthase kinase 3β (GSK3β), plays a pivotal role in regulating the inflammatory response of macrophages and neutrophils in mammals ( 5 , 6 ). (frontiersin.org)
  • GSK3β is unique among kinases in that it is constitutively active in resting cells and its activity can be inhibited by serine phosphorylation by a variety of cellular functions including apoptosis, glycogen metabolism, microtubule function, and cell motility ( 7 , 8 ). (frontiersin.org)
  • Scratch-wound healing was also associated with glycogen synthase kinase 3β (GSK3β)/β-catenin signaling, which was further enhanced by hypoxia. (aspetjournals.org)
  • Another important signaling pathway that may contribute to the regulation of wound healing involves glycogen synthase kinase 3β (GSK3β) and β-catenin. (aspetjournals.org)
  • Glycogen synthase kinase-3β (GSK3β) is a serine/threonine protein kinase that plays an important role in renal tubular injury and regeneration in acute kidney injury. (biologists.org)
  • The glycogen synthase kinase-3 (GSK3) family of protein kinases consists of GSK3α and GSK3β isoforms, and plays an important role in injury and repair of renal tubular epithelial cells in AKI. (biologists.org)
  • Lithium, a direct inhibitor of glycogen synthase kinase 3 (GSK3) activity, and a mainstay in BPD therapeutics, has been proposed to target GSK3 as a mechanism of mood stabilization. (jcircadianrhythms.com)
  • GSK3, an essential kinase with widespread roles in development, cell survival, and metabolism has been demonstrated to be an essential component of theDrosophilacircadian clock. (jcircadianrhythms.com)
  • Resveratrol increased inhibitory phosphorylation of glycogen synthase kinase-3β (GSK3β) downstream of AMPK, which contributed to mitochondrial protection and cell survival. (aspetjournals.org)
  • Glycogen Synthase Kinase 3 (GSK3) is an important component of the WNT pathway and is involved in regulating β-catenin stability and expression of WNT target genes. (le.ac.uk)
  • The serine/threonine kinase glycogen synthase kinase-3 (GSK3) plays an important role in balancing pro- and anti-inflammatory cytokines. (immune-source.com)
  • The serine/threonine kinase glycogen synthase kinase-3 (GSK3) offers been demonstrated to have an important part in regulating IL-10 manifestation 10,11. (immune-source.com)
  • The glycogen synthase kinase 3 (GSK3)/SHAGGY-like kinases (GSKs) are non-receptor serine/threonine protein kinases that are involved in a variety of biological processes. (biomedcentral.com)
  • In contrast to the two members of the GSK3 family found in mammals, plants appear to have a much larger set of divergent GSK3/SHAGGY-like kinase genes [ 12 - 28 ], with functions as numerous as in animals. (biomedcentral.com)
  • Regulation of FAK Ser-722 phosphorylation and kinase activity by GSK3 and PP1 during cell spreading and migration. (semanticscholar.org)
  • Glycogen synthase kinase-3α (GSK3α) is a protein kinase that participates in the regulation of mitochondrial activity. (aging-us.com)
  • Glycogen Synthase Kinase 3 (GSK3) is involved in a myriad of signalling pathways and has recently received considerable interest due to its conflicting roles tumourigenesis. (nuigalway.ie)
  • Glycogen synthase kinase 3β (GSK3β) has emerged as a common therapeutic target in more than 25 different cancer types. (jcmtjournal.com)
  • In this study, we identified that glycogen synthase kinase-3 (GSK3) differentially regulates 5-HT1Rs. (semanticscholar.org)
  • Glycogen synthase kinase-3 (GSK3): regulation, actions, and diseases. (semanticscholar.org)
  • Mammalian glycogen synthase kinase-3 (GSK3) is generated from two genes, GSK3alpha and GSK3beta, while a splice variant of GSK3beta (GSK3beta2), containing a 13 amino acid insert, is enriched in neurons. (brad.ac.uk)
  • The present invention relates to a novel mechanism for regulating GSK3 kinases, including BIN2 and human GSK3-beta, by dephosphorylating GSK3 kinases through the PP1 phosphatase, such as the plant BSU1 phosphatases and human PP1-gamma. (patentsencyclopedia.com)
  • 40. A method for treating a disease associated with abnormal cell growth comprising contacting a cell comprising glycogen synthase kinase 3 (GSK3) protein with a PP1 phosphatase or a homolog thereof in an amount effective to dephosphoylate the GSK3 protein. (patentsencyclopedia.com)
  • Glycogen Synthase Kinase 3 (GSK-‑3) is a serine/threonine protein kinase and one of several protein kinases, which phosphorylate glycogen synthase. (neb.com)
  • GSK-3β is a ubiquitous cytosolic serine/threonine protein kinase that has been implicated in multiple receptor-mediated intracellular processes ( 3 ). (diabetesjournals.org)
  • GSK3B is a multifunctional serine/threonine kinase which has been implicated in multiple biological processes including embryonic development, cell differentiation, apoptosis and insulin response. (atlasgeneticsoncology.org)
  • Glycogen synthase kinase 3β (GSK 3β), a multifunctional serine and threonine kinase, plays a critical role in a variety of cellular activities, including signaling transduction, protein and glycogen metabolism, cell proliferation, cell differentiation, and apoptosis. (spandidos-publications.com)
  • Glycogen synthase kinase-3 (GSK-3) is a serine-threonine kinase that exists as two isoforms, alpha and beta, encoded by separate genes. (nih.gov)
  • Over activity of Glycogen synthase kinase-3β (GSK-3β), a serine/threonine-protein kinase has been implicated in a number of diseases including stroke, type II diabetes and Alzheimer disease (AD). (springer.com)
  • However, many known O -GlcNAc attachment sites are similar or identical to those used by serine/threonine kinases for phosphorylation, particularly by the proline-directed kinases. (mcponline.org)
  • GSK-3β belongs to a family of GSK-3, a multifunctional serine/threonine kinase ( 12 ) that has been implicated in multiple biological processes including embryonic development, cell differentiation, apoptosis, and insulin response ( 13 , 14 ). (aacrjournals.org)
  • Several kinases including Akt can attenuate GSK-3β enzymatic activity by phosphorylating the NH 2 -terminal serine, Ser 9 ( 13 ). (aacrjournals.org)
  • Glycogen synthase kinase-3 (GSK-3) is a ubiquitous serine/threonine protein kinase that phosphorylates glycogen synthase and numerous other substrates. (hindawi.com)
  • Both isoforms are active in resting cells, and phosphorylation by serine-21 (GSK-3 α ) or serine-9 (GSK-3 β ) via the phosphatidylinositol 3-kinase (PI3K)/Akt pathway inhibits its activity [ 1 ]. (hindawi.com)
  • Ionizing radiation, which leads to p53 accumulation, directed phosphorylation of GSK-3 at serine 9, which preceded and overlapped with the increase in p53 levels. (thebiogrid.org)
  • Moreover, expression of a GSK-3 mutant where serine 9 was replaced with an alanine reduced the accumulation of p53 and induction of its target p21(WAF-1). (thebiogrid.org)
  • Glycogen synthase kinase-3β (GSK-3β), a serine/threonine protein kinase involved in glycogen metabolism and the Wnt signaling pathway, plays important roles in embryonic development and tumorigenesis. (aacrjournals.org)
  • Unlike human glycogen synthase kinase 3β, DWF12 lacks the conserved serine-9 residue in the auto-inhibitory N terminus. (plantphysiol.org)
  • Glycogen synthase kinase 3β (GSK-3β) is a serine/threonine protein kinase that has recently emerged as a key regulatory switch in the modulation of the inflammatory response. (ovid.com)
  • The cytoplasmic serine/threonine protein kinase glycogen synthase kinase-3 (GSK-3) was first described as a component of the metabolic pathway for glycogen synthase regulation ( 4 ). (aacrjournals.org)
  • While the etiology of insulin resistance is multifactorial, one factor associated with reduced insulin action is enhanced activity of the serine/threonine kinase glycogen synthase kinase-3 (GSK-3) in skeletal muscle, liver, and adipose tissue. (eurekaselect.com)
  • Studies utilizing highly selective GSK-3 inhibitors indicate that GSK-3 overactivity in obesity is associated with enhanced IRS-1 serine phosphorylation and defective IRS-1- dependent signaling, ultimately resulting in reduced GLUT-4 translocation and glucose transport activity in skeletal muscle. (eurekaselect.com)
  • Glycogen synthase kinase (GSK)-3 is a ubiquitous serine-threonine protein kinase that participates in a multitude of cellular processes and signal transduction pathways. (ovid.com)
  • A major effector of the PI3K signal in all cells types is the serine/threonine kinase Akt, also known as protein kinase B (PKB). (aacrjournals.org)
  • GSK-3 is a proline-directed serine/threonine kinase, considered as a key influencer in these pathologies. (currentenzymeinhibition.com)
  • Glycogen synthase kinase-3 (GSK-3) is a serine/threonine kinase regulating diverse cellular functions including metabolism, transcription and cell survival. (ox.ac.uk)
  • Numerous intracellular signalling pathways converge on GSK-3 and regulate its activity via inhibitory serine-phosphorylation. (ox.ac.uk)
  • Glycogen synthase kinase 3 (GSK-3) belongs to a highly conserved family of protein serine/threonine kinase whose members in high eukaryotes are involved in hormonal regulation, nuclear signaling, and cell fate determination. (elsevier.com)
  • Rsks are serine/threonine kinases and are activated by the MAPK/ERK pathway. (wikipedia.org)
  • Glycogen synthase kinase 3-alpha EC 2.7.1.37 is a multifunctional protein serine kinase, homologous to Drosophila 'shaggy' (zeste-white3) and implicated in the control of several regulatory proteins including glycogen synthase and various transcription factors (e.g. (wikipedia.org)
  • A GSK-3 inhibitor, BIO, promoted the growth of human outer root sheath cells, which could be cultured for up to four passages. (nih.gov)
  • To investigate whether kinase inhibition can reduce tauopathy and the degeneration associated with it in vivo , transgenic mice overexpressing mutant human tau were treated with the glycogen synthase kinase-3 (GSK-3) inhibitor lithium chloride. (pnas.org)
  • Administration of a second GSK-3 inhibitor also correlated with reduced insoluble tau levels, supporting the idea that lithium exerts its effect through GSK-3 inhibition. (pnas.org)
  • Lithium, a medication for bipolar disorder, is a direct ( 17 ) and indirect ( 18 , 19 ) inhibitor of GSK-3. (pnas.org)
  • Raf kinase inhibitory protein (RKIP) is a physiologic inhibitor of c-RAF kinase and nuclear factor κB signaling that represses tumor invasion and metastasis. (nih.gov)
  • We assessed the effect of low to high doses of a GSK-3 β inhibitor on survival and apoptosis of the NSC-34 motor neuron-like cell line after serum withdrawal. (hindawi.com)
  • The GSK-3 β inhibitor had an antiapoptotic effect at the low dose but was proapoptotic at the high dose. (hindawi.com)
  • Our results suggest that GSK-3 β inhibitor dose may determine the summation effect of the intrinsic and extrinsic apoptosis pathways. (hindawi.com)
  • The extrinsic apoptosis pathway might be another therapeutic target for developing a potential GSK-3 β inhibitor. (hindawi.com)
  • Anti-obesity effects of 3-hydroxychromone derivative, a novel small-molecule inhibitor of glycogen synthase kinase-3. (sigmaaldrich.com)
  • Therefore, this research focused on identification and characterization of a novel small-molecule GSK-3 inhibitor. (sigmaaldrich.com)
  • Compound 1a, a structure based on 3-hydroxychromone bearing isothiazolidine-1,1-dione, was identified from chemical library as a highly potent GSK-3 inhibitor. (sigmaaldrich.com)
  • From these results, it can be concluded that compound 1a, a novel small-molecule inhibitor of GSK-3, has potential as a new class of therapeutic agent for obesity treatment. (sigmaaldrich.com)
  • The challenge for glycogen synthase kinase-3 (GSK-3) inhibitor design lies in achieving high selectivity for one isoform over the other. (tu-darmstadt.de)
  • The expression of proinflammatory molecules in the presence of the GSK-3β inhibitor CHIR 99021 was analyzed using RT-PCR, western blot, and ELISA. (arvojournals.org)
  • Lithium, alsterpaullone or valproate, three independent glycogen synthase kinase-3 inhibitors, but not butyrolactone 1, an inhibitor of cyclin-dependent protein kinases, induced mitochondrial clustering in association with tau dephosphorylation. (biologists.org)
  • Furthermore, this LKB1-dependent mitochondrial protection resulted from resveratrol's poly(ADP-ribose)polymerase activation, but not SIRT1 activation, as supported by the experiment using 3-aminobenzamide, a poly(ADP-ribose)polymerase inhibitor. (aspetjournals.org)
  • In the treatment group, the potent and selective GSK-3[beta] inhibitor 4-benzyl-2-methyl-1,2,4-thiadiazolidine-3,5-dione (TDZD-8) was administered 1 hr and 6 hrs after the first injection of cerulein (10 mg/kg, intraperitoneally). (ovid.com)
  • Inhibition of GSK-3β using short hairpin RNA or a selective inhibitor potently blocks breast cancer cell migration concomitant with a reduction in NFAT activity. (aacrjournals.org)
  • These are bound to regulatory subunits, such as inhibitor 2 (I2) in the cytosol and G in the glycogen and microsomal fractions. (semanticscholar.org)
  • a known GSK-3β inhibitor. (ijpsdr.com)
  • [8] One exception is Tideglusib [9] , an ATP-non competitive GSK-3β inhibitor that reached phase II clinical trials for cognitive disorders (Alzheimer's disease and Progressive Supranuclear Palsy). (ijpsdr.com)
  • Rizzieri DA, Cooley S, Odenike O, Moonan L, Chow KH, Jackson K, Wang X, Brail L, Borthakur G. An open-label phase 2 study of glycogen synthase kinase-3 inhibitor LY2090314 in patients with acute leukemia. (uchicago.edu)
  • Chemically distinct GSK-3 inhibitors (AR-A014418, TDZD-8, and 9-ING-41) suppressed the growth of neuroblastoma cells, whereas 9-ING-41, a clinically relevant small-molecule GSK-3ß inhibitor with broad-spectrum preclinical antitumor activity, being the most potent. (northwestern.edu)
  • TWS119 is inhibitor of glycogen synthase kinase-3β with IC50 of 30 nM. (csnpharm.cn)
  • Tideglusib is an irreversible GSK-3 inhibitor with IC50 of 5 nM and 60 nM for GSK-3βWT (1 h preincubation) and GSK-3βC199A (1 h preincubation), respectively. (csnpharm.cn)
  • TDZD-8, the derivative of thiadiazolidinone, is a selective inhibitor of GSK-3. (csnpharm.cn)
  • SB-216763 is potent and selective glycogen synthase kinase-3 (GSK-3) inhibitor (Ki = 9 nM) and competes with ATP. (csnpharm.cn)
  • LY2090314 is a potent inhibitor of glycogen synthase kinase-3 (GSK-3) with IC50s of 1.5 nM and 0.9 nM for GSK-3α and GSK-3β respectively. (csnpharm.cn)
  • Kenpaullone is an ATP-competitive inhibitor of CDK1/cyclin B (IC50 = 0.4 µM), CDK2/cyclin A (IC50 = 0.68 µM), CDK5/p25 (IC50 = 0.85 µM), lymphocyte kinase (IC50 = 0.47 µM) , and GSK-3β (C50 = 0.23 μM). (csnpharm.cn)
  • Indirubin-3'-monoxime is a powerful inhibitor of GSK-3β with IC50 of 22nM, also inhibits CDK1/5 (IC50 = 180/100 nM). (csnpharm.cn)
  • IM-12 is a GSK-3β inhibitor with IC50 of 53 nM. (csnpharm.cn)
  • GSK-3 inhibitor 1 is a potent GSK-3 inhibitor. (csnpharm.cn)
  • CP21R7 is a slective inhibitor of GSK-3β. (csnpharm.cn)
  • CHIR-99021 hydrochloride is hydrochloride of CHIR-99021, which is a GSK-3α/β inhibitor with IC50 of 10 nM/6.7 nM and shows greater than 500-fold selectivity for GSK-3 versus its closest homologs Cdc2 and ERK2. (csnpharm.cn)
  • CHIR-98014 (CT98014) is highly selective aminopyrimidine-derivatived inhibitor of GSK-3 with IC50 of 650nM and 580nM for GSK-3 and GSK-3(measured by kinase assays), respectively, and exhibits >1000-fold selectivity for GSK-3 over closely related kinases, such as cdc2. (csnpharm.cn)
  • BIO is an inhibitor of GSK-3 and CDK1-cyclinB complex. (csnpharm.cn)
  • Bikinin acts as an ATP-competitive inhibitor of arabidopsis GSK-3 and effective activator of brassinosteroid (BR) signaling. (csnpharm.cn)
  • AZD2858 is an inhibitor of GSK-3 with IC50 of 68 nM that can inhibit the tau phosphorylation of S396 site and activate Wnt signaling pathway. (csnpharm.cn)
  • 5-bromoindole is an inhibitor of glycogen synthase kinase 3 (GSK-3), it can be used as important pharmaceutical chemical intermediate. (csnpharm.cn)
  • The present study tested the hypothesis that in vitro treatment of skeletal muscle with lithium chloride (LiCl), a glycogen synthase kinase (GSK) 3 inhibitor, would reverse both the sepsis-induced increase in muscle protein degradation and inhibition of protein synthesis. (elsevier.com)
  • The glycogen synthase kinase-3 (GSK-3) inhibitor SB216763 activated an efficient mitochondrial biogenesis program in control cortical neurons and counteracted the OGD-mediated mitochondrial biogenesis impairment. (elsevier.com)
  • These Temsirolimus enzyme inhibitor tests uncovered that T-betCdeficient BMMCs adhered badly to both VCAM-1 and MAdCAM-1 (Fig. 3). (healthyguide.info)
  • The LTP deficits can be attenuated/rescued by chronic treatment with lithium, a GSK-3 inhibitor. (ox.ac.uk)
  • Furthermore, the neuron-enriched GSK3beta2 variant phosphorylates phospho-glycogen synthase 2 peptide, CRMP2 (Thr509/514), CRMP4 (Thr509), Inhibitor-2 (Thr72) and tau (Ser396), at a lower rate than GSK3beta1. (brad.ac.uk)
  • Regulates protein synthesis by controlling the activity of initiation factor 2B (EIF2BE/EIF2B5) in the same manner as glycogen synthase. (uniprot.org)
  • Regulates glycogen metabolism in liver, but not in muscle. (uniprot.org)
  • Glycogen synthase kinase-3 (GSK-3) regulates TGF-β(1) -induced differentiation of pulmonary fibroblasts. (biomedsearch.com)
  • CONCLUSION AND IMPLICATION: We demonstrate that GSK-3 signaling regulates TGF-β(1) -induced myofibroblast differentiation by regulating CREB phosphorylation. (biomedsearch.com)
  • Furthermore, our data suggest that GSK-3β regulates the hypertrophic response, at least in part, by modulating the nuclear/cytoplasmic partitioning of a member of the nuclear factor of activated T cells family of transcription factors. (rupress.org)
  • The list of putative substrates of GSK-3 suggested that this kinase might also play a negative modulatory role in hypertrophy since it negatively regulates the actions of major targets of two cytosolic signaling pathways that have been implicated in the hypertrophic response to pressure overload in the intact animal. (rupress.org)
  • Glycogen synthase kinase 3-dependent phosphorylation of Mdm2 regulates p53 abundance. (thebiogrid.org)
  • Glycogen synthase kinase 3 regulates cell fate in Dictyostelium. (acris-antibodies.com)
  • We have shown recently that glycogen synthase kinase-3 (GSK-3) β regulates nuclear factor-κB (NF-κB)-mediated pancreatic cancer cell survival and proliferation in vitro . (aacrjournals.org)
  • Our results show the antitumor effect of GSK-3 inhibition in vivo , identify GSK-3β nuclear accumulation as a hallmark of poorly differentiated pancreatic adenocarcinoma, and provide new insight into the mechanism by which GSK-3β regulates NF-κB activity in pancreatic cancer. (aacrjournals.org)
  • The phosphoinositide 3-kinase (PI3K) pathway regulates a multitude of cellular processes. (aacrjournals.org)
  • Post-translational modification of GSK-3 by multiple substrates further regulates downstream messengers and their response in multiple pathologies. (currentenzymeinhibition.com)
  • The dopamine D2 receptor regulates Akt and GSK-3 via Dvl-3. (semanticscholar.org)
  • This interaction of phospho SOS1 and 14-3-3 negatively regulates Ras-MAPK pathway. (wikipedia.org)
  • These results indicate that GSK-3beta is expressed in hair bulge stem cells and BIO promotes the growth of ORS cells, possibly by regulating the GSK-3 signaling pathway. (nih.gov)
  • RESULTS- STAT3 was found to sensitize the insulin signaling through suppression of GSK-3β, a negative regulator of insulin signaling pathway. (diabetesjournals.org)
  • The unique feature that distinguishes GSK-3β from other protein kinases is that it is constitutively active in resting conditions and acts as a suppressor in the insulin signaling pathway ( 2 ). (diabetesjournals.org)
  • Using a phospho-specific antibody array confirmed the phosphorylation of GSK-3β (Ser9) as well as the phosphorylation of the downstream cytokine-activated intracellular signaling pathway involved in stimulating immune responses, IκB, the IκB subunit IKK-β, and the NF-κB subunits p105, p65, and c-Rel. (frontiersin.org)
  • Taken together, these findings demonstrated that LiCl promoted apoptosis in NB4 cells through the Akt signaling pathway and that G2/M phase arrest was induced by increase of p-GSK-3β(S9). (medsci.org)
  • Glycogen synthase kinase-3β (GSK-3β), a key component of the Wnt signaling pathway, is involved in multiple physiologic processes such as protein synthesis, tumorigenesis, and apoptosis. (aacrjournals.org)
  • The phosphoinositide 3-kinase (PI3K) signaling pathway controls a variety of biological functions including cell survival, proliferation, and migration. (aacrjournals.org)
  • Consequently, inhibition of GSK-3β activity has been proposed to play a role in the regulation of the NF-κB signaling pathway that elicits cellular survival responses. (biomedcentral.com)
  • Here we show that glycogen synthase kinase 3β (GSK-3β) is required for radiation-induced hippocampal neuronal apoptosis and subsequent neurocognitive decline. (aacrjournals.org)
  • Inhibition of GSK-3β either by small molecules (SB216763 or SB415286) or by ectopic expression of kinase-inactive GSK-3β before irradiation significantly attenuated radiation-induced apoptosis in hippocampal neurons. (aacrjournals.org)
  • GSK-3β inhibition with SB216763 or SB415286 also decreased apoptosis in the subgranular zone of the hippocampus in irradiated mice, leading to improved cognitive function in irradiated animals. (aacrjournals.org)
  • Studies of the molecular mechanisms of the cytoprotective effect showed that GSK-3β activity in hippocampal neurons was not significantly altered by radiation, pointing to the indirect involvement of this enzyme in radiation-induced apoptosis. (aacrjournals.org)
  • Glycogen synthase kinase-3 β (GSK-3 β ) inhibitors have been suggested as a core regulator of apoptosis and have been investigated as therapeutic agents for neurodegenerative diseases, including amyotrophic lateral sclerosis. (hindawi.com)
  • However, GSK-3 β has an interesting paradoxical effect of being proapoptotic during mitochondrial-mediated intrinsic apoptosis but antiapoptotic during death receptor-mediated extrinsic apoptosis. (hindawi.com)
  • This implicates GSK-3 as a multifunctional modulator in critical cellular processes, including cell metabolism, gene expression, cell cycle division, development, and apoptosis [ 1 , 2 ]. (hindawi.com)
  • In addition, aberrant GSK-3 β activity has been suggested as a potential etiology associated with neuronal apoptosis in ALS. (hindawi.com)
  • Prodigiosin-induced apoptosis was recovered by inhibiting GSK-3β, which might be due, at least in part, to the blockade of the GSK-3β-dependent up-regulation of death receptors 4 and 5 expression. (aacrjournals.org)
  • These findings suggest that prodigiosin-mediated GSK-3β activation is a key event in regulating the molecular pathways that trigger the apoptosis induced by this anticancer agent. (aacrjournals.org)
  • The antiapoptotic Bcl-2-like proteins, including Bcl-2, Bcl-xL, and myeloid cell leukemia-1 (Mcl-1), which share three or four Bcl-2 homology (BH) regions (BH1-BH4), are required for cell survival and have been found to play key roles in the development of cancer due to their role in controlling mitochondria-mediated intrinsic pathways of apoptosis ( 2 , 3 ). (aacrjournals.org)
  • Recent studies have shown that overexpression of GSK-3β can induce apoptosis in several cell types, whereas inactivation of GSK-3β through phosphorylation of the Ser 9 residue can reduce apoptosis ( 14 , 15 ), indicating that GSK-3β may play a critical role in linking multiple pathways to regulate cellular apoptosis. (aacrjournals.org)
  • Surprisingly, similar to the disruption of the NF-κB p65 or IκB kinase β genes, ablation of the murine GSK-3β gene resulted in embryonic lethality due to hepatocyte apoptosis and massive liver degeneration ( 6 - 8 ). (aacrjournals.org)
  • We have shown previously that activation of AMP-activated protein kinase (AMPK) protects hepatocytes from AA + iron-induced apoptosis. (aspetjournals.org)
  • Both pharmacological and genetic inactivation of GSK-3β significantly decreased ACD, while activation of GSK-3β increased autophagic flux and caused more cell death without inducing apoptosis following insulin withdrawal. (biomedcentral.com)
  • The absence of apoptotic indices in GSK-3β-induced cell death in insulin-deprived HCN cells corroborates the notion that HCN cell death following insulin withdrawal represents the genuine model of ACD in apoptosis-intact mammalian cells and identifies GSK-3β as a key negative effector of NSC survival downstream of insulin signaling. (biomedcentral.com)
  • Inhibition of GSK-3 resulted in a decreased expression of the antiapoptotic molecule XIAP and an increase in neuroblastoma cell apoptosis. (northwestern.edu)
  • Here, we investigated the relationship between GSK-3β inhibition and NF-κB in apoptosis of pediatric primary leukemia cells obtained from 39 newly diagnosed ALL children in China. (biomedcentral.com)
  • These results indicate that inhibition of GSK-3β downregulates the NF-κB activation pathway, leading to suppression of the expression of an NF-κB-regulated gene and promotion of apoptosis in ALL cells in vitro. (biomedcentral.com)
  • GSK-3β inhibition leads to suppression of NF-κB transcriptional activity and induces apoptosis through the transcriptional downregulation of the survivin gene. (biomedcentral.com)
  • GSK-3 phosphorylates several exogenous substrates, but not on Tyr residues (5,6). (neb.com)
  • In vitro work has shown that GSK-3β phosphorylates tau at multiple sites, and some of these sites are abnormally phosphorylated in neurodegenerative disease ( 7 , 9 ). (pnas.org)
  • Herein, we report that glycogen synthase kinase-3β (GSK-3β), a protein kinase previously implicated in processes as diverse as development and tumorigenesis, is inactivated by hypertrophic stimuli via a phosphoinositide 3-kinase-dependent protein kinase that phosphorylates GSK-3β on ser 9. (rupress.org)
  • Fatty acids (FAs) upregulate GSK-3α, which phosphorylates PPARα at Ser280 in the ligand-binding domain (LBD). (cdc.gov)
  • Here, we show that the glycogen synthase kinase (GSK) 3Β, which phosphorylates the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10), is selectively enriched in nucleoli of RAS-transformed cells. (nyu.edu)
  • Summers SA, Kao AW, Kohn AD, Backus GS, Roth RA, Pessin JE and Birnbaum MJ: The role of glycogen synthase kinase 3beta in insulin-stimulated glucose metabolism. (spandidos-publications.com)
  • Glycogen synthase kinase 3 (GSK-3) plays a central role in cellular energy metabolism, and dysregulation of GSK-3 activity is implicated in a variety of metabolic disorders, including obesity, type 2 diabetes, and cancer. (sigmaaldrich.com)
  • Glycogen synthase kinase 3 has evolutionarily conserved roles in cell signaling and metabolism and is a recognized drug target in neurological pathologies, most prominently bipolar disorder. (rsc.org)
  • A glycogen synthase kinase that was originally described as a key enzyme involved in glycogen metabolism. (uchicago.edu)
  • OBJECTIVE- Glucose homeostasis is achieved by triggering regulation of glycogen synthesis genes in response to insulin when mammals feed, but the underlying molecular mechanism remains largely unknown. (diabetesjournals.org)
  • In addition, chronic lithium induces molecular changes consistent with inhibition of GSK-3 within regions of the brain that are paralleled in Gsk-3 β +/- heterozygous mice. (jneurosci.org)
  • In addition, molecular changes associated with the inhibition of GSK-3 are observed in vivo in both lithium-treated and Gsk-3 β +/- mice. (jneurosci.org)
  • Woodgett JR: Molecular cloning and expression of glycogen synthase kinase-3/factor A. EMBO J. 9:2431-2438. (spandidos-publications.com)
  • A CoMFA analysis was also performed highlighting the molecular electrostatic field interaction in the interaction of TDZDs with GSK-3. (ub.edu)
  • In mamm als, GSK-3 is encoded by two genes known as gsk-3 α and gsk-3 β , encoding GSK-3 α (483 aa in humans) and GSK - 3 β (433 aa) proteins with apparent molecular masses of 51 and 47kDa, respectively. (acris-antibodies.com)
  • In molecular biology, ribosomal s6 kinase (rsk) is a family of protein kinases involved in signal transduction. (wikipedia.org)
  • Remarkably, these lithium-sensitive behaviors are also observed in mice lacking one copy of the gene encoding glycogen synthase kinase-3 β ( Gsk-3 β), a well established direct target of lithium. (jneurosci.org)
  • Our findings indicate that these candidate GSK-3 substrates can influence all levels of gene expression including chromatin modulators, transcription factors, RNA binding proteins, splicing factors, translational initiators and cell cycle regulators. (upenn.edu)
  • Using adenovirus-mediated gene transfer of GSK-3β containing a ser 9 to alanine mutation, which prevents inactivation by hypertrophic stimuli, we demonstrate that inactivation of GSK-3β is required for cardiomyocytes to undergo hypertrophy. (rupress.org)
  • Inhibition of GSK-3β activity therefore leads to stabilization and accumulation of β-catenin in the cytosol, which is shuttled into the nucleus where it functions to regulate gene expression. (aacrjournals.org)
  • G93A and A4V mutant human Cu, Zn-superoxide dismutase (hSOD1) gene-transfected motor neurons consistently display GSK-3 β hyperactivity along with inhibition of the PI3K/Akt pathway [ 11 ]. (hindawi.com)
  • A microarray-assisted gene expression screen of chicken heterophils revealed glycogen synthase kinase-3β (GSK-3β), a multifunctional Ser/Thr kinase, to be consistently upregulated 30-180 min following stimulation with Salmonella enterica serovar Enteritidis ( S . Enteritidis). (frontiersin.org)
  • After homologous recombination with the targeting vector, exon 2 (E2) of the GSK-3β gene was replaced with a LoxP-flanked (floxed) exon 2 and an FRT-flanked neomycin resistance cassette. (asm.org)
  • Map-based cloning of the DWF12 gene revealed that DWF12 belongs to a member of the glycogen synthase kinase 3β family. (plantphysiol.org)
  • The BRI1 gene was isolated and shown to encode a Leu-rich repeat receptor protein kinase ( Li and Chory, 1997 ). (plantphysiol.org)
  • Expression of the GSK-3β gene in whole orbital tissue explants was compared between GO and non-GO donors using quantitative real-time PCR (RT-PCR). (arvojournals.org)
  • GSK-3 is involved in numerous cellular functions, including glycogen synthesis, protein synthesis, gene transcription, and cell differentiation. (eurekaselect.com)
  • GSK-3β inhibition significantly decreased the expression of the NF-κB target gene survivin . (biomedcentral.com)
  • Glycogen synthase kinase-3 alpha is an enzyme that in humans is encoded by the GSK3A gene. (wikipedia.org)
  • AR-A014418 protects N2A neuroblastoma cells against cell death mediated by inhibition of the phosphatidylinositol 3-kinase/protein kinase B survival pathway. (rcsb.org)
  • Physiologically, insulin signals through a pathway involving protein kinases including, but not limited to, phosphatidylinositol 3-kinase, AKT or protein kinase B (PKB), and glycogen synthase kinase (GSK)-3β (the phosphatidylinositol 3-kinase/Akt/GSK-3β pathway) ( 1 ). (diabetesjournals.org)
  • GSK-3β activity can be abrogated by direct phosphorylation on the Ser 9 residue by phosphatidylinositol 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK)/p90RSK, or mammalian target of rapamycin/S6K upon a number of extracellular stimuli, such as insulin, epidermal growth factor, and fibroblast growth factor ( 13 ). (aacrjournals.org)
  • Previously published data suggest that CK2 and GSK-3 act synergistically to promote the phosphatidylinositol-3 kinase (PI3K) pathway via phosphorylation of PTEN. (elsevier.com)
  • The activation of Akt, PI3K, nuclear factor (NF)-κB, Erk, Jnk, and p38 kinase by IL-1β and TNF-α was diminished with CHIR 99021 in GO cells. (arvojournals.org)
  • A major effector of PI3K is Akt/protein kinase B (PKB). (aacrjournals.org)
  • The signaling mechanisms leading to Akt/PKB activation by PI3K, and subsequent activation of downstream secondary signaling cascades leading to physiologic responses, have been characterized in considerable detail (reviewed in ref. 3 ). (aacrjournals.org)
  • Together, these data suggest that the CK2 and GSK-3 pathways regulate AKT/PI3K signaling in leukemia via two complementary mechanisms: a) direct phosphorylation of PTEN and b) transcriptional regulation of PI3K-promoting genes. (elsevier.com)
  • Recent studies found that neurofilaments, amyloid precursor protein, and tau proteins are substrates of GSK-3 and that aberrant phosphorylation of these proteins is implicated in pathologies of the nervous system. (nih.gov)
  • Over 100 putative GSK-3 substrates have been reported, based on direct kinase assays or genetic and pharmacological manipulation of GSK-3, in diverse cell types. (upenn.edu)
  • We have therefore used a large-scale mass spectrometry approach to analyze global changes in phosphorylation and describe the repertoire of GSK-3 substrates in a single cell type. (upenn.edu)
  • Taken together, the research in this dissertation represents the first unbiased analysis of GSK-3 phosphorylation substrates in a single cell type and provides the first evidence of GSK-3 as a general regulator of alternative splicing. (upenn.edu)
  • Signal transducers and activators of transcription (STAT) proteins comprise a family of transcription factors latent in the cytoplasm that consists of seven different members: STAT1, -2, -3, -4, -5A, -5B, and -6 ( 8 , 9 ). (diabetesjournals.org)
  • Quantitative measurements indicated that at least 10 proteins had an apparent increase of O -GlcNAcylation upon GSK-3 inhibition by lithium, whereas surprisingly 19 other proteins showed decreases. (mcponline.org)
  • O -GlcNAc is ubiquitous on nuclear and cytoplasmic proteins in all multicellular eukaryotes ( 3 ). (mcponline.org)
  • To further validate our top hits, we conducted in vitro kinase assays with recombinant proteins and identified the splicing factor RBM8A and an RNA processing protein NPM1 to be direct targets of GSK-3. (upenn.edu)
  • Taken together, these data rule out an effect of GSK-3β on the cascade of proteins that culminates in phosphorylation of IκBα and its degradation and suggest that GSK-3β may regulate the nuclear activity of NF-κB p65/p50. (aacrjournals.org)
  • Implicated in the hormonal control of several regulatory proteins including glycogen synthase, MYB and the transcription factor JUN (By similarity). (biomol.com)
  • Mammalian GSK-3 exists as two isoforms, α and β, and, unlike most protein kinases, it is constitutively active in neurons ( 7 , 8 ). (pnas.org)
  • GSK-3 usually exists in two isoforms, GKS-3 α and GSK-3 β , in mammals. (hindawi.com)
  • There are two homologous mammalian isoforms encoded by different genes, GSK-3α and GSK-3β ( 5 ). (aacrjournals.org)
  • Distinct mechanisms were reported to explain the distinct functions of Akt/PKB isoforms in the regulation of invasive migration, including differential regulation of the extracellular signal-regulated kinase pathway ( 6 ) and tuberous sclerosis complex 2 ( 8 ). (aacrjournals.org)
  • Activation of protein phosphatase-1 isoforms and glycogen synthase kinase-3 beta in muscle from mdx mice. (semanticscholar.org)
  • Glycogen synthase kinase 3 comprises two isoforms (GSK-3α and GSK-3β) that are implicated in type II diabetes, neurodegeneration, and cancer. (monash.edu)
  • We conclude that GSK-3 isoforms exhibit tissue-specific physiological functions and that GSK-3α KO mice are insulin sensitive, reinforcing the potential of GSK-3 as a therapeutic target for type II diabetes. (monash.edu)
  • Two homologous mammalian GSK-3 isoforms are encoded by different genes, GSK-3α and GSK-3β . (biomedcentral.com)
  • Soutar MP, Kim WY, Williamson R et al (2010) Evidence that glycogen synthase kinase-3 isoforms have distinct substrate preference in the brain. (brad.ac.uk)
  • The role of glycogen synthase kinase 3 beta in the transformation of epidermal cells. (cdc.gov)
  • The recent discovered role of glycogen synthase kinase-3 homologue, GskA, in A. fumigatus human infection and our previous experience on human GSK-3 inhibitors focus our attention on this kinase as a target for the development of antifungal drugs. (csic.es)
  • We sought to determine the role of glycogen synthase kinase-3β (GSK-3β) in the pathogenesis of Graves' orbitopathy(GO). (arvojournals.org)
  • Cociova OM, Li B, NomanBhoy T, Li Q, Nakamura A, Nomura M, Okada K et al (2017) Synthesis and structure-activity relationship of 4-quinolone-3-carboxylic acid based inhibitors of glycogen synthase kinase-3β. (springer.com)
  • Phosphorylation of Tyr216 located in the T-loop (activation site) facilitates substrate phosphorylation by GSK3B but is not strictly required for its kinase activity. (atlasgeneticsoncology.org)
  • Phosphorylation of GSK3B at Ser9 in N-terminal region leads to inhibition of its kinase activity. (atlasgeneticsoncology.org)
  • Glycogen synthase kinase-3 beta (GSK3B) was named due to its ability to phosphorylate and inactivate glycogen synthase. (atlasgeneticsoncology.org)
  • Nuclear and mitochondrial localization of GSK3B correlates with its higher kinase activity compared to cytosolic protein. (atlasgeneticsoncology.org)
  • GSK3B is a multifunctional protein kinase which is implicated in a large number of cellular processes and diseases. (atlasgeneticsoncology.org)
  • Thotala DK and Yazlovitskaya EM: GSK3B (glycogen synthase kinase 3 beta). (spandidos-publications.com)
  • Isolated from a strain of E. coli that carries a clone expressing GSK-3β derived from a rabbit skeletal muscle cDNA library (kindly provided by Dr. P. J. Roach) (5). (neb.com)
  • In skeletal muscle, contributes to insulin regulation of glycogen synthesis by phosphorylating and inhibiting GYS1 activity and hence glycogen synthesis. (uniprot.org)
  • Embi N, Rylatt DB and Cohen P: Glycogen synthase kinase-3 from rabbit skeletal muscle. (spandidos-publications.com)
  • Evidence from muscle and fat cell lines and in skeletal muscle from a variety of obese rodent models and from type 2 diabetic humans supports a role of GSK-3 overactivity in the development of insulin resistance of glucose transport and glycogenesis. (eurekaselect.com)
  • Recent studies have demonstrated that oxidative stress, resulting from enhanced exposure to oxidants, causes impaired insulin signaling and insulin resistance of skeletal muscle glucose transport, in part due to reduced suppression of GSK-3 activity and increased IRS-1 Ser307 phosphorylation. (eurekaselect.com)
  • The evidence to date supports an important role of GSK-3 dysfunction in the multifactorial etiology of insulin resistance in skeletal muscle. (eurekaselect.com)
  • Transgenic mice overexpressing GSK-3β display tau hyperphosphorylation, disrupted microtubules, and apoptotic neurons ( 11 ). (pnas.org)
  • To test the effect of LiCl on pathogenic tau formation in vivo , we have treated JNPL3 transgenic mice overexpressing mutant human tau ( 26 ) with two GSK-3 inhibitors. (pnas.org)
  • During feeding, both mRNA and protein levels of GSK-3β decreased in Stat3 f/+ mice, which reflected the need of hepatocytes for insulin to induce glycogen synthesis. (diabetesjournals.org)
  • In contrast, the L-Stat3 −/− mice lost this control and showed a monophasic increase in the GSK-3β level in response to insulin. (diabetesjournals.org)
  • Administration of GSK-3β inhibitors lithium chloride and L803-mts restored glucose homeostasis and rescued the glucose intolerance and impaired insulin response in L-Stat3 −/− mice. (diabetesjournals.org)
  • Male C57BL/6 mice were intraperitoneally injected with 1-methyl4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) for 7 d to induce PD. (nature.com)
  • Additionally, mice were treated with either 5 or 10 mg/kg DHM for a total of 13 d (3 d before the start of MPTP, during MPTP administration (7 d) and 3 d after the end of MPTP). (nature.com)
  • We found that lithium alters specific behaviors in a manner that is paralleled in mice lacking one copy of Gsk-3 β. (jneurosci.org)
  • Generation of conditional GSK-3β-floxed (FL), targeted mice. (asm.org)
  • A) Schematic outline describing the targeting strategy for generating conditional GSK-3β-floxed (FL) mice and the subsequent tissue-specific KO mice. (asm.org)
  • Mice carrying the GSK-3β-floxed allele were bred to FLPe recombinase-expressing mice to remove the neo cassette. (asm.org)
  • Deletion of exon 2, and hence deletion of GSK-3β expression, is achieved by crossing GSK-3β FL mice with strains expressing Cre recombinase under the control of tissue-specific promoters. (asm.org)
  • ES cells and mouse tail genomic DNA were digested with BglII and probed with the 5′ GSK-3β or neomycin DNA probe (*), confirming proper targeting of the GSK-3β-floxed allele in R1 mouse ES cell (mES) clones 1B9 and 2D12 and germ line transmission of the GSK-3β-floxed allele (by use of the 1B9 clone) in mice. (asm.org)
  • Generation and characterization of liver-specific GSK-3β KO (LβKO) mice. (asm.org)
  • Male GSK-3β FL/FL (termed FL/FLβ) control and GSK-3β FL/FL AlbCre + (termed LβKO) mice were weighed every 2 weeks between the ages of 4 and 24 weeks. (asm.org)
  • PCR for GSK-3β (top) demonstrates that exon 2 of the GSK-3β FL allele is excised only in the livers of the LβKO mice, not in those of the control FL/FLβ or the WT AlbCre +/+ (littermate control) mice. (asm.org)
  • Tissue extracts from liver, muscle (quadricep) and brain were prepared from 8-week-old male mice of the genotypes indicated and immunoblotted with an antibody that specifically recognizes GSK-3α and GSK-3β. (asm.org)
  • Here we investigate the effects of GSK-3[beta] inhibition on the development of experimental acute pancreatitis induced by cerulein in mice. (ovid.com)
  • Here, we report the generation of mice lacking GSK-3α. (monash.edu)
  • Fasted and glucose-stimulated hepatic glycogen content was enhanced in GSK-3α KO mice, whereas muscle glycogen was unaltered. (monash.edu)
  • SIRT3 Blocks Aging-Associated Tissue Fibrosis in Mice by Deacetylating and Activating Glycogen Synthase Kinase 3ß. (uchicago.edu)
  • Abnormal phosphorylation of tau by kinases or phosphatases has been proposed as a pathogenic mechanism in tangle formation. (pnas.org)
  • 5. Kinase-Kinase and Site-Site Interactions in the Phosphorylation of Tau by GSK-3. (wiley.com)
  • These findings raise the possibility that the phosphorylation of tau by glycogen synthase kinase-3 might be involved in the regulation of organelle transport. (biologists.org)
  • In the present study, we show that in PC12 cells differentiated by nerve growth factor (NGF) or FGF-2, the expression of GSK-3β and tau and the phosphorylation of tau are upregulated. (biologists.org)
  • Glycogen Synthase Kinase (GSK)-3β is a kinase, responsible for phosphorylation of tau, activation of which can be induced by phosphorylated double-stranded RNA dependent protein kinase (pPKR). (soton.ac.uk)
  • However, a journey to the clinic with a series of highly selective and potent small molecule GSK-3β targeted therapy is still a challenging task. (ijpsdr.com)
  • Ser/Thr phosphorylation causes inactivation, and Tyr phosphorylation results in increased activity (Y216 for GSK-3β). (neb.com)
  • Fang X, Yu SX, Lu Y, Bast RC Jr, Woodgett JR and Mills GB: Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A. Proc Natl Acad Sci USA. (spandidos-publications.com)
  • The potential effects of compound 1a on the inactivation of GSK-3 were confirmed in human liver HepG2 and human embryonic kidney HEK293 cells. (sigmaaldrich.com)
  • Our results indicate that Mcl-1 stabilization by GSK-3β inactivation could be involved in tumorigenesis and serve as a useful prognostic marker for human breast cancer. (aacrjournals.org)
  • Our studies show that activation of Akt/PKB leads to inactivation of the effector GSK-3β and the outcome of this signaling event is degradation of NFAT by the proteasome and subsequent inhibition of cell migration. (aacrjournals.org)
  • Gong Y , Zhang Z , Chang Z , Zhou H , Zhao R , He B , . Inactivation of glycogen synthase kinase-3α is required for mitochondria-mediated apoptotic germ cell phagocytosis in Sertoli cells. (aging-us.com)
  • The lower GSK-3β expression generated by Aβ immunotherapy shows evidence of a modification of the signalling pathway induced by GSK-3β leading to the overall reduction of tau, supporting the contention that in humans, GSK-3β unifies Aβ and tau-related neuropathology. (soton.ac.uk)
  • There are three variants of p90rsk in humans, rsk 1-3. (wikipedia.org)
  • However, GSK 3β is controversial due to its bifacial roles of tumor suppression and activation. (spandidos-publications.com)
  • Moreover, prodigiosin caused AKT dephosphorylation and glycogen synthase kinase-3β (GSK-3β) activation, which correlated with NAG-1 expression. (aacrjournals.org)
  • Furthermore, we found that activation of GSK-3β could down-regulate Mcl-1 and was required for proteasome-mediated Mcl-1 degradation. (aacrjournals.org)
  • Under some physiologic conditions, such as UV irradiation, anticancer drug treatment, and inhibition of growth factor pathways, Mcl-1 was down-regulated through activation of GSK-3β. (aacrjournals.org)
  • Activation of NF-κB in human cancer has been shown to positively influence cancer cell survival, proliferation, invasion, metastasis, and chemoresistance ( 2 , 3 ). (aacrjournals.org)
  • These findings suggest a role for GSK-3β (but not GSK-3α) in the mechanism of NF-κB activation and suggest that GSK-3β may be a potential therapeutic target in human cancer. (aacrjournals.org)
  • Using GSK-3β-deficient mouse embryonic fibroblasts, it was shown that the early steps leading to NF-κB activation following TNF-α treatment (degradation of IκBα and translocation of NF-κB to the nucleus) were unaffected by the loss of GSK-3β, indicating that NF-κB is regulated by GSK-3β at the level of the transcriptional complex ( 8 ). (aacrjournals.org)
  • Consistent with this idea, we have shown recently that GSK-3β participates in NF-κB-mediated pancreatic cancer cell survival and proliferation in vitro by regulating NF-κB activity at a point downstream of the activation of the IκB kinase complex ( 9 ). (aacrjournals.org)
  • These findings indicate that epithelial cells must sustain activation of a specific kinase to impede a mesenchymal transition. (rupress.org)
  • These findings suggest a role for GSK-3β (but not GSK-3α) in the regulation of NF-κB activation. (biomedcentral.com)
  • EGF and TPA-stimulated Ser9 phosphorylation was mediated by phosphoinositide-3-kinase (Pl3K)/Akt and protein kinase C (PKC) pathways. (cdc.gov)
  • Jacobs KM, Bhave SR, Ferraro DJ, Jaboin JJ, Hallahan DE and Thotala D: GSK-3β: A bifunctional role in cell death pathways. (spandidos-publications.com)
  • Here we report the O -GlcNAc perturbations in response to inhibition of glycogen synthase kinase-3 (GSK-3), a pivotal kinase involved in many signaling pathways. (mcponline.org)
  • Glycogen Synthase Kinase-3 (GSK-3) is a constitutively active, ubiquitously expressed kinase that acts as a critical regulator of many signaling pathways. (upenn.edu)
  • In this manuscript we review the crosstalk between the Casein Kinase II (CK2) and Glycogen Synthase Kinase-3 (GSK-3) pathways that plays a critical role in the regulation of cellular proliferation in leukemia. (elsevier.com)
  • It also plays a role in the WNT and phosphoinositide 3-kinase (especially PIK3CG) signaling pathways. (wikipedia.org)
  • To analyse the organisation of these two genes, a YAC library was screened by polymerase chain reaction, using primers specific for human GSK-3 alpha and GSK-3 beta cDNA. (nih.gov)
  • GSK-3 has been highly conserved during evolution, and homolog genes have been identified in virtually every eukaryotic genome investigated. (acris-antibodies.com)
  • GSK-3 mRNA and protein are involved in transcribing a variety of genes that are involved in the progression of pathology. (currentenzymeinhibition.com)
  • Likewise, small interfering RNA knockdown of LKB1, an upstream kinase of AMPK, reduced the ability of resveratrol to protect cells from mitochondrial dysfunction. (aspetjournals.org)
  • Two proline-directed kinases, glycogen synthase kinase-3 (GSK-3) and cyclin-dependent kinase-5 are thought to be key factors in abnormal tau phosphorylation (reviewed in refs. (pnas.org)
  • Selective inhibitors of Plasmodium falciparum glycogen synthase-3 (PfGSK-3): New antimalarial agents? (cambridge.org)
  • We have identified 7 new indirubin analogues that are selective inhibitors of L GSK-3 over L CRK3. (biomedcentral.com)
  • The present study demonstrated that DHM is a potent neuroprotective agent for DA neurons by modulating the Akt/GSK-3β pathway, which suggests that DHM may be a promising therapeutic candidate for PD. (nature.com)
  • 15. 3-Amino Pyrazoles as Potent and Selective Glycogen Synthase (GSK-3) Inhibitors. (wiley.com)
  • The results obtained in this study can be useful to design potent inhibitors of GSK-3β. (springer.com)
  • [6] In the course of recent decades several diverse heterocyclic compounds and novel chemotypes have been reported as potent GSK-3β modulators. (ijpsdr.com)
  • GSK-3 expressed in E. coli or insect cells is extensively phosphorylated on Tyr. (neb.com)
  • In mammalian cells, cotransfection of tau with GSK-3β leads to increased tau phosphorylation and microtubule rearrangement ( 9 , 10 ). (pnas.org)
  • However, in primary rodent cells activated Ras induces premature senescence (oncogene-induced senescence), decreasing oncogenesis ( 3 ⇓ - 5 ). (pnas.org)
  • Chiara F and Rasola A: GSK-3 and mitochondria in cancer cells. (spandidos-publications.com)
  • Beurel E (2011) Regulation by glycogen synthase kinase-3 of inflammation and T cells in CNS diseases. (springer.com)
  • Unlike most protein kinases, GSK-3 is active in the unstimulated cell and becomes inactivated when cells are stimulated by a variety of mitogens or by the Wnt/wingless pathway ( Woodgett 1994 ). (rupress.org)
  • GSK-3β is ubiquitously expressed in eukaryotic cells and is highly enriched in the brain and has been implicated in central nervous system dysfunctions like Alzheimer's disease ( 15 ), schizophrenia ( 16 ), dopamine-associated behaviors ( 17 ), bipolar disorders ( 18 ), and Parkinson's disease ( 19 ). (aacrjournals.org)
  • During infection or injury, IL-33 acts as an alarmin and is released from injured or dying host cells ( 3 , 4 ). (jimmunol.org)
  • Our objective was to determine the localization of GSK-3β in pancreatic cancer cells and assess the antitumor effect of GSK-3 inhibition in vivo to improve our understanding of the mechanism by which GSK-3β affects NF-κB activity in pancreatic cancer. (aacrjournals.org)
  • We have found that active GSK-3β can accumulate in the nucleus of pancreatic cancer cells and that inhibition of GSK-3 kinase activity represses its nuclear accumulation via proteasomal degradation within the nucleus. (aacrjournals.org)
  • However, whether GSK-3β can be accumulated in the nuclei of cancer cells where it can contribute to NF-κB transcriptional activity is not known. (aacrjournals.org)
  • The localization of GSK-3β in human cancer cells and the mechanism by which GSK-3β affects NF-κB activity has not yet been determined. (aacrjournals.org)
  • 2 , 3 In response to the inflammatory cells that infiltrate the space, fibroblasts proliferate and secrete proinflammatory cytokines, actively inciting and perpetuating inflammation. (arvojournals.org)
  • We found that in PC12 cells treated with NGF or fibroblast growth factor-2, glycogen synthase kinase-3β and tau were upregulated simultaneously from around day 2 of differentiation, with increasing glycogen synthase kinase-3-mediated tau phosphorylation. (biologists.org)
  • We identify NFκB as a transcription factor inhibited by GSK-3 in epithelial cells that is relevant for Snail expression. (rupress.org)
  • Keywords: Compact disc4+ Testosterone levels?cells, Epigenetic, Glycogen synthase kinase-3, IL-10 Launch IL-10 is necessary for security from immunopathology, allergies, and autoimmunity and is expressed by a wide range of adaptive and innate defense cells 1,2. (immune-source.com)
  • In this study, we demonstrate that glycogen synthase kinase 3β (GSK-3β) induces ACD in insulin-deprived HCN cells. (biomedcentral.com)
  • Collectively, these data demonstrate that GSK-3β is a key regulator of ACD in HCN cells following insulin withdrawal. (biomedcentral.com)
  • This reversal of selectivity in Leishmania parasites compared to mammalian cells makes the design of specific indirubin-based L GSK-3 inhibitors difficult. (biomedcentral.com)
  • We used immunofluorescence staining to detect nuclear GSK-3β in these cells. (biomedcentral.com)
  • GSK-3β significantly accumulates in the nuclei of ALL cells than in the nuclei of control cells. (biomedcentral.com)
  • Cell death induced by GSK-3β inhibition in ALL cells was mediated by a downregulation of NF-κB p65 transcriptional activity. (biomedcentral.com)
  • In the present study, we demonstrated that GSK-3β accumulates in the nuclei of primitive pediatric ALL cells from the BM. (biomedcentral.com)
  • Naito S, Bilim V, Yuuki K, Ugolkov A, Motoyama T, Nagaoka A, Kato T and Tomita Y: Glycogen synthase kinase-3beta: A prognostic marker and a potential therapeutic target in human bladder cancer. (spandidos-publications.com)
  • Eldar-Finkelman H (2002) Glycogen synthase kinase 3: an emerging therapeutic target. (springer.com)
  • Glycogen synthase kinase-3ß (GSK-3ß) is a potential therapeutic target in neuroblastoma. (northwestern.edu)
  • Furthermore, our findings suggest that GSK-3β or NF-κB is a potential therapeutic target in the treatment of pediatric ALL. (biomedcentral.com)
  • An in vitro kinase assay utilizing a panel of kinases demonstrated that compound 1a strongly inhibits GSK-3β. (sigmaaldrich.com)
  • Using a specific GSK-3β ELISA assay, 30 min after infection with S . Enteritidis, heterophils had a significant decrease ( p ≤ 0.05) in total GSK-3β, but a significant increase ( p ≤ 0.05) in phosphorylated GSK-3β (Ser9). (frontiersin.org)
  • We studied the effect of GSK-3 inhibition on tumor growth, cancer cell proliferation, and survival in established CAPAN2 tumor xenografts using a tumor regrowth delay assay, Western blotting, bromodeoxyuridine incorporation, and terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling. (aacrjournals.org)
  • Description: Evaluated in a Kinase-Glo assay. (guidetopharmacology.org)
  • A novel compound [7,10-dioxo-4,5-dihydro-7H,10H-pyrano[3,2,1-ij]quinolin-8-yl acetate] proposed from docking results in the substrate site of GSK-3β was found to have inhibitory activity (IC 50 ) above 100μM concentration in ADP-Glo TM Kinase assay. (ijpsdr.com)
  • A new in-house indirubin library, composed of 35 compounds, initially designed to target mammalian kinases (CDKs, GSK-3), was tested against Leishmania donovani promastigotes and intracellular amastigotes using the Alamar blue assay. (biomedcentral.com)
  • After treatment with chemically distinct GSK-3β inhibitors in vitro, NF-κB transcriptional activity was identified by means of western blotting and electrophoretic mobility shift assay (EMSA). (biomedcentral.com)
  • The aim of our study was to examine the role of the signal transducers and activators of transcription 3 (STAT3) in insulin signaling. (diabetesjournals.org)
  • CONCLUSIONS- These data indicate that STAT3 sensitizes insulin signaling by negatively regulating GSK-3β. (diabetesjournals.org)
  • Unlike the other members of the pathway, GSK-3β is a key negative regulator in insulin signaling ( 2 ). (diabetesjournals.org)
  • The fact that the function of two key targets of insulin action, glycogen synthase and insulin receptor substrate-1 (IRS-1), are suppressed by GSK-3β ( 4 - 6 ) and the fact that GSK-3β activity is higher in diabetic tissues ( 7 ) make it a promising drug discovery target for insulin resistance and type 2 diabetes. (diabetesjournals.org)
  • Cross DA, Alessi DR, Cohen P, Andjelkovich M and Hemmings BA: Inhibition of glycogen synthase kinase-3 by insulin mediated by protein kinase B. Nature. (spandidos-publications.com)
  • GSK-3 remains an important target for interventions designed to improve insulin action in obesity-associated insulin resistance and type 2 diabetes. (eurekaselect.com)
  • GSK-3 activity is elevated in human and rodent models of diabetes, and various GSK-3 inhibitors improve glucose tolerance and insulin sensitivity in rodent models of obesity and diabetes. (monash.edu)
  • Unlike GSK-3β mutants, which die before birth, GSK-3α knockout (GSK-3α KO) animals are viable but display enhanced glucose and insulin sensitivity accompanied by reduced fat mass. (monash.edu)
  • Insulin-stimulated protein kinase B (PKB/Akt) and GSK-3β phosphorylation was higher in GSK-3α KO livers compared to wild-type littermates, and IRS-1 expression was markedly increased. (monash.edu)
  • Treatment resulted in significant inhibition of GSK-3 activity. (pnas.org)
  • 25 ) have recently shown that lithium chloride (LiCl) significantly decreases β-amyloid (Aβ) production in vivo through inhibition of GSK-3 activity. (pnas.org)
  • Buescher JL, Phiel CJ (2010) A non catalytic domain of glycogen synthase kinase-3 (GSK-3) is essential for activity. (springer.com)
  • At the same time, radiation led to increased accumulation of p53, whereas inhibition of the basal level of GSK-3β activity before radiation prevented p53 accumulation, suggesting a possible mechanism of cytoprotection by GSK-3β inhibitors. (aacrjournals.org)
  • This allowed us to study the structure-activity relationship of the library members as well as the chemical genetic relationships between kinase targets. (rsc.org)
  • S . Enteritidis interaction with heterophils alters GSK-3β activity by stimulating phosphorylation at Ser9 and that peaks by 30 min post-infection. (frontiersin.org)
  • Our findings suggest that the repression of GSK-3 activity is beneficial to the host cell and may act as a target for treatment in controlling intestinal colonization in chickens. (frontiersin.org)
  • In the current study, we found that the activity of GSK-3β was required for proteasome-mediated Mcl-1 degradation, and that Mcl-1 inversely correlated with GSK-3β activity and associated with poor prognosis in human breast cancer. (aacrjournals.org)
  • Among 15 novel compounds, compound 27 showed high activity against GSK-3α/β with the highest GSK-3α selectivity reported to date. (tu-darmstadt.de)
  • GSK-3β-mediated inhibition of NFAT activity is due to proteasomal degradation. (aacrjournals.org)
  • We report that the activity of glycogen synthase kinase-3 (GSK-3) is necessary for the maintenance of the epithelial architecture. (rupress.org)
  • Sepsis decreased GSK-3β phosphorylation and increased GSK-3β activity, under basal conditions. (elsevier.com)
  • Incubation of septic muscle with LiCl completely reversed the increased GSK-3β activity and decreased proteolysis to basal nonseptic values, but only partially reduced proteosome activity and did not diminish atrogene expression. (elsevier.com)
  • phosphorylation, decreased eIF2B activity, or the reduced phosphorylation of FOXO3, but instead was more closely associated with the continued suppression of mTOR (mammalian target of rapamycin) kinase activity (e.g., reduced phosphorylation of 4E-BP1 and S6). (elsevier.com)
  • Indirubins with antileishmanial activity were tested against L GSK-3 and L CRK3 kinases, purified from homologous expression systems. (biomedcentral.com)
  • Glycogen synthase kinase-3β (GSK-3β) has recently been found to positively regulate the activity of nuclear factor-κB (NF-κB). (biomedcentral.com)
  • [0002] The present invention relates to the use of phosphatase activity to regulate protein kinases. (patentsencyclopedia.com)
  • The protein sequences of family members are highly conserved throughout the kinase domain. (biomedcentral.com)
  • [7] Unlike other kinases, the ATP-binding site of GSK-3β is highly conserved. (ijpsdr.com)
  • Constitutively active protein kinase that acts as a negative regulator in the hormonal control of glucose homeostasis, Wnt signaling and regulation of transcription factors and microtubules, by phosphorylating and inactivating glycogen synthase (GYS1 or GYS2), CTNNB1/beta-catenin, APC and AXIN1. (uniprot.org)
  • Constitutively active GSK-3α, but not GSK-3β, was sufficient to drive PPARα signaling, while cardiac-specific knockdown of GSK-3α, but not GSK-3β, or replacement of PPARα Ser280 with Ala conferred resistance to lipotoxicity in the heart. (cdc.gov)
  • Herein, we hypothesized that the occurrence of IVH would downregulate Wnt signaling, and that activating Wnt signaling by GSK-3β inhibition or Wnt3A recombinant human protein (rh-Wnt3A) treatment might promote maturation of OPCs, myelination of the white matter, and neurological recovery in premature rabbits with IVH. (elsevier.com)
  • Here, we present evidence that implicates GSK-3 in synaptic plasticity. (ox.ac.uk)
  • Dysregulation of GSK-3 plays an important role in the pathogenesis of various human diseases including psychiatric disorders, cancer, diabetics, inflammatory disease, and neurodegenerative diseases, including amyotrophic lateral sclerosis (ALS) [ 3 - 5 ]. (hindawi.com)
  • Dysregulation of GSK-3β has been implicated in the pathogenesis of several diseases including sepsis. (ovid.com)
  • She has been and still is an active researcher in the design and synthesis of GSK-3 inhibitors. (wiley.com)
  • We hypothesized that inhibition of a specific kinase would cause a perturbation to O -GlcNAcylation. (mcponline.org)
  • 2. Glycogen-Synthase-Kinase-β (GSK-3β) a Key Signaling Enzyme: A Developmental Neurobiological Perspective. (wiley.com)
  • Monoclonal antibody 4G-1E was generated against the non-phosphorylated catalytic domain (between sub-domain VII and VIII) of the Drosophila GSK-3 / shaggy enzyme, corresponding to residues 268-284 in GSK-3 α and 205-221 in GSK-3 β, respectively. (acris-antibodies.com)
  • The substrate specificity of GSK-3 is unique and substrate dependent. (neb.com)
  • In conclusion, 3 ' -bulky amino substituted 6-BIO derivatives, which demonstrate enhanced specificity towards L GSK-3, represent a new scaffold for targeted drug development to treat leishmaniasis. (biomedcentral.com)
  • Grimes CA and Jope RS: The multifaceted roles of glycogen synthase kinase 3beta in cellular signaling. (spandidos-publications.com)
  • The inhibition of the kinase attenuated the proinflammatory cytokines production and fibroblast differentiation into adipocytes. (arvojournals.org)
  • Among a number of downstream targets, β-catenin is phosphorylated by GSK-3β and then degraded through the ubiquitin-proteasome system ( 20 ). (aacrjournals.org)
  • Stabilization of glycogen synthase and β-catenin, which are direct targets of GSK-3, by compound 1a was assessed in comparison with two other GSK-3 inhibitors: LiCl and SB-415286. (sigmaaldrich.com)
  • Both CK2 and GSK-3 are potential targets for anti-leukemia treatment. (elsevier.com)
  • Inhibiting multiple targets respective to the disease concerned, along with GSK-3 inhibition may have more therapeutic benefits than inhibiting alone GSK-3 alone. (currentenzymeinhibition.com)