Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.Protein Kinase C: 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.Cyclic AMP-Dependent Protein Kinases: 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.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Calcium-Calmodulin-Dependent Protein Kinases: 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)Phosphatidylinositol 3-Kinases: 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.Enzyme Activation: 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.Protein Kinase Inhibitors: Agents that inhibit PROTEIN KINASES.Signal Transduction: 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.Protein-Serine-Threonine Kinases: A group of enzymes that catalyzes the phosphorylation of serine or threonine residues in proteins, with ATP or other nucleotides as phosphate donors.Calcium-Calmodulin-Dependent Protein Kinase Type 2: A multifunctional calcium-calmodulin-dependent protein kinase subtype that occurs as an oligomeric protein comprised of twelve subunits. It differs from other enzyme subtypes in that it lacks a phosphorylatable activation domain that can respond to CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE.Calcium-Calmodulin-Dependent Protein Kinase Type 1: A monomeric calcium-calmodulin-dependent protein kinase subtype that is expressed in a broad variety of mammalian cell types. Its expression is regulated by the action of CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE. Several isoforms of this enzyme subtype are encoded by distinct genes.Calcium: A basic element found in nearly all organized tissues. It is a member of the alkaline earth family of metals with the atomic symbol Ca, atomic number 20, and atomic weight 40. Calcium is the most abundant mineral in the body and combines with phosphorus to form calcium phosphate in the bones and teeth. It is essential for the normal functioning of nerves and muscles and plays a role in blood coagulation (as factor IV) and in many enzymatic processes.Cyclic GMP-Dependent Protein Kinases: A group of cyclic GMP-dependent enzymes that catalyze the phosphorylation of SERINE or THREONINE residues of proteins.Cyclic AMP: 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.Phosphatidylinositols: Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to the hexahydroxy alcohol, myo-inositol. Complete hydrolysis yields 1 mole of glycerol, phosphoric acid, myo-inositol, and 2 moles of fatty acids.Mitogen-Activated Protein Kinases: 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).Molecular Sequence Data: 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.Isoenzymes: Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.Calmodulin: 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.MAP Kinase Signaling System: 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.Enzyme Inhibitors: Compounds or agents that combine with an enzyme in such a manner as to prevent the normal substrate-enzyme combination and the catalytic reaction.Amino Acid Sequence: 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.Paramecium tetraurelia: A species of ciliate protozoa. It is used in biomedical research.Kinetics: The rate dynamics in chemical or physical systems.p38 Mitogen-Activated Protein Kinases: 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.Cell Line: Established cell cultures that have the potential to propagate indefinitely.Cells, Cultured: 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.eIF-2 Kinase: 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.Tetradecanoylphorbol Acetate: A phorbol ester found in CROTON OIL with very effective tumor promoting activity. It stimulates the synthesis of both DNA and RNA.Protein Kinase C-alpha: A cytoplasmic serine threonine kinase involved in regulating CELL DIFFERENTIATION and CELLULAR PROLIFERATION. Overexpression of this enzyme has been shown to promote PHOSPHORYLATION of BCL-2 PROTO-ONCOGENE PROTEINS and chemoresistance in human acute leukemia cells.Mitogen-Activated Protein Kinase 1: 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.Protein Binding: 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.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.Cyclic AMP-Dependent Protein Kinase Catalytic Subunits: Specific enzyme subunits that form the active sites of the type I and type II cyclic-AMP protein kinases. Each molecule of enzyme contains two catalytic subunits.Mitogen-Activated Protein Kinase Kinases: 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.Mitogen-Activated Protein Kinase 3: 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.Cyclic GMP: Guanosine cyclic 3',5'-(hydrogen phosphate). A guanine nucleotide containing one phosphate group which is esterified to the sugar moiety in both the 3'- and 5'-positions. It is a cellular regulatory agent and has been described as a second messenger. Its levels increase in response to a variety of hormones, including acetylcholine, insulin, and oxytocin and it has been found to activate specific protein kinases. (From Merck Index, 11th ed)Protein Kinase C-delta: A ubiquitously expressed protein kinase that is involved in a variety of cellular SIGNAL PATHWAYS. Its activity is regulated by a variety of signaling protein tyrosine kinase.Cyclic AMP-Dependent Protein Kinase Type II: A cyclic AMP-dependent protein kinase subtype primarily found in particulate subcellular fractions. They are tetrameric proteins that contain two catalytic subunits and two type II-specific regulatory subunits.Proto-Oncogene Proteins c-akt: 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.Mutation: 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.JNK Mitogen-Activated Protein Kinases: 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.PhosphoproteinsCalcium-Binding Proteins: Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS.Blotting, Western: 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.Isoquinolines: A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)Phosphoprotein Phosphatases: 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)Transfection: 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.Peptide T: N-(N-(N(2)-(N-(N-(N-(N-D-Alanyl L-seryl)-L-threonyl)-L-threonyl) L-threonyl)-L-asparaginyl)-L-tyrosyl) L-threonine. Octapeptide sharing sequence homology with HIV envelope protein gp120. It is potentially useful as antiviral agent in AIDS therapy. The core pentapeptide sequence, TTNYT, consisting of amino acids 4-8 in peptide T, is the HIV envelope sequence required for attachment to the CD4 receptor.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Phosphatidylinositol Phosphates: Phosphatidylinositols in which one or more alcohol group of the inositol has been substituted with a phosphate group.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Serine: 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.1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: A specific protein kinase C inhibitor, which inhibits superoxide release from human neutrophils (PMN) stimulated with phorbol myristate acetate or synthetic diacylglycerol.Cyclic GMP-Dependent Protein Kinase Type I: A cyclic GMP-dependent protein kinase subtype that is expressed in SMOOTH MUSCLE tissues and plays a role in regulation of smooth muscle contraction. Two isoforms, PKGIalpha and PKGIbeta, of the type I protein kinase exist due to alternative splicing of its mRNA.AMP-Activated Protein Kinases: 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.Androstadienes: Derivatives of the steroid androstane having two double bonds at any site in any of the rings.Cattle: Domesticated bovine animals of the genus Bos, usually kept on a farm or ranch and used for the production of meat or dairy products or for heavy labor.Adenosine Triphosphate: An adenine nucleotide containing three phosphate groups esterified to the sugar moiety. In addition to its crucial roles in metabolism adenosine triphosphate is a neurotransmitter.src-Family Kinases: 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.Cyclic AMP-Dependent Protein Kinase RIalpha Subunit: A type I cAMP-dependent protein kinase regulatory subunit that plays a role in confering CYCLIC AMP activation of protein kinase activity. It has a lower affinity for cAMP than the CYCLIC-AMP-DEPENDENT PROTEIN KINASE RIBETA SUBUNIT.Recombinant Fusion Proteins: 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.Nucleotides, CyclicProtein-Tyrosine Kinases: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.ChromonesProtamine Kinase: An aspect of protein kinase (EC 2.7.1.37) in which serine residues in protamines and histones are phosphorylated in the presence of ATP.Protein Kinase C-epsilon: A protein kinase C subtype that was originally characterized as a CALCIUM-independent, serine-threonine kinase that is activated by PHORBOL ESTERS and DIACYLGLYCEROLS. It is targeted to specific cellular compartments in response to extracellular signals that activate G-PROTEIN-COUPLED RECEPTORS; TYROSINE KINASE RECEPTORS; and intracellular protein tyrosine kinase.Protein Kinase C beta: PKC beta encodes two proteins (PKCB1 and PKCBII) generated by alternative splicing of C-terminal exons. It is widely distributed with wide-ranging roles in processes such as B-cell receptor regulation, oxidative stress-induced apoptosis, androgen receptor-dependent transcriptional regulation, insulin signaling, and endothelial cell proliferation.1-Phosphatidylinositol 4-Kinase: An enzyme that catalyzes the conversion of phosphatidylinositol (PHOSPHATIDYLINOSITOLS) to phosphatidylinositol 4-phosphate, the first committed step in the biosynthesis of phosphatidylinositol 4,5-bisphosphate.Benzylamines: Toluenes in which one hydrogen of the methyl group is substituted by an amino group. Permitted are any substituents on the benzene ring or the amino group.Rats, Sprague-Dawley: 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.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Cyclic GMP-Dependent Protein Kinase Type II: A cyclic GMP-dependent protein kinase subtype that is expressed predominantly in INTESTINES, BRAIN, and KIDNEY. The protein is myristoylated on its N-terminus which may play a role its membrane localization.Cell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.Calcium-Calmodulin-Dependent Protein Kinase Type 4: A monomeric calcium-calmodulin-dependent protein kinase subtype that is primarily expressed in neuronal tissues; T-LYMPHOCYTES and TESTIS. The activity of this enzyme is regulated by its phosphorylation by CALCIUM-CALMODULIN-DEPENDENT PROTEIN KINASE KINASE.Cytosol: Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.MorpholinesApoptosis: 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.RNA, Messenger: 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.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Models, Biological: 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.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.Sequence Homology, Amino Acid: The degree of similarity between sequences of amino acids. This information is useful for the analyzing genetic relatedness of proteins and species.Phospholipids: Lipids containing one or more phosphate groups, particularly those derived from either glycerol (phosphoglycerides see GLYCEROPHOSPHOLIPIDS) or sphingosine (SPHINGOLIPIDS). They are polar lipids that are of great importance for the structure and function of cell membranes and are the most abundant of membrane lipids, although not stored in large amounts in the system.Gene Expression Regulation, Enzymologic: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in enzyme synthesis.Proto-Oncogene Proteins: 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.Protein Structure, Tertiary: 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.Phosphotransferases (Alcohol Group Acceptor): A group of enzymes that transfers a phosphate group onto an alcohol group acceptor. EC 2.7.1.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Rabbits: 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.Gene Expression Regulation: 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.Class Ib Phosphatidylinositol 3-Kinase: A phosphatidylinositol 3-kinase subclass that includes enzymes formed through the association of a p110gamma catalytic subunit and one of the three regulatory subunits of 84, 87, and 101 kDa in size. This subclass of enzymes is a downstream target of G PROTEIN-COUPLED RECEPTORS.CDC2 Protein Kinase: 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.Electrophoresis, Polyacrylamide Gel: Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.Membrane Proteins: Proteins which are found in membranes including cellular and intracellular membranes. They consist of two types, peripheral and integral proteins. They include most membrane-associated enzymes, antigenic proteins, transport proteins, and drug, hormone, and lectin receptors.Sulfonamides: A group of compounds that contain the structure SO2NH2.Molecular Weight: The sum of the weight of all the atoms in a molecule.Myocardium: 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.Calcium Signaling: Signal transduction mechanisms whereby calcium mobilization (from outside the cell or from intracellular storage pools) to the cytoplasm is triggered by external stimuli. Calcium signals are often seen to propagate as waves, oscillations, spikes, sparks, or puffs. The calcium acts as an intracellular messenger by activating calcium-responsive proteins.Cloning, Molecular: The insertion of recombinant DNA molecules from prokaryotic and/or eukaryotic sources into a replicating vehicle, such as a plasmid or virus vector, and the introduction of the resultant hybrid molecules into recipient cells without altering the viability of those cells.Catalytic Domain: The region of an enzyme that interacts with its substrate to cause the enzymatic reaction.Phosphatidylserines: Derivatives of phosphatidic acids in which the phosphoric acid is bound in ester linkage to a serine moiety. Complete hydrolysis yields 1 mole of glycerol, phosphoric acid and serine and 2 moles of fatty acids.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.MAP Kinase Kinase Kinases: 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).Intracellular Signaling Peptides and Proteins: 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.Extracellular Signal-Regulated MAP Kinases: 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.Proteins: 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.Casein Kinase II: 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.Diglycerides8-Bromo Cyclic Adenosine Monophosphate: A long-acting derivative of cyclic AMP. It is an activator of cyclic AMP-dependent protein kinase, but resistant to degradation by cyclic AMP phosphodiesterase.Ribosomal Protein S6 Kinases: 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.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.p21-Activated Kinases: 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.Colforsin: Potent activator of the adenylate cyclase system and the biosynthesis of cyclic AMP. From the plant COLEUS FORSKOHLII. Has antihypertensive, positive inotropic, platelet aggregation inhibitory, and smooth muscle relaxant activities; also lowers intraocular pressure and promotes release of hormones from the pituitary gland.Type C Phospholipases: A subclass of phospholipases that hydrolyze the phosphoester bond found in the third position of GLYCEROPHOSPHOLIPIDS. Although the singular term phospholipase C specifically refers to an enzyme that catalyzes the hydrolysis of PHOSPHATIDYLCHOLINE (EC 3.1.4.3), it is commonly used in the literature to refer to broad variety of enzymes that specifically catalyze the hydrolysis of PHOSPHATIDYLINOSITOLS.3-Phosphoinositide-Dependent Protein Kinases: Highly conserved protein-serine threonine kinases that phosphorylate and activate a group of AGC protein kinases, especially in response to the production of the SECOND MESSENGERS, phosphatidylinositol 3,4,-biphosphate (PtdIns(3,4)P2) and phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3).Cell Line, Tumor: A cell line derived from cultured tumor cells.RNA, Double-Stranded: RNA consisting of two strands as opposed to the more prevalent single-stranded RNA. Most of the double-stranded segments are formed from transcription of DNA by intramolecular base-pairing of inverted complementary sequences separated by a single-stranded loop. Some double-stranded segments of RNA are normal in all organisms.Tumor Cells, Cultured: 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.Peptides: Members of the class of compounds composed of AMINO ACIDS joined together by peptide bonds between adjacent amino acids into linear, branched or cyclical structures. OLIGOPEPTIDES are composed of approximately 2-12 amino acids. Polypeptides are composed of approximately 13 or more amino acids. PROTEINS are linear polypeptides that are normally synthesized on RIBOSOMES.MAP Kinase Kinase 1: An abundant 43-kDa mitogen-activated protein kinase kinase subtype with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.Phorbol 12,13-Dibutyrate: A phorbol ester found in CROTON OIL which, in addition to being a potent skin tumor promoter, is also an effective activator of calcium-activated, phospholipid-dependent protein kinase (protein kinase C). Due to its activation of this enzyme, phorbol 12,13-dibutyrate profoundly affects many different biological systems.Protein Transport: 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.Immunoblotting: 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.Phosphatidylinositol 4,5-Diphosphate: A phosphoinositide present in all eukaryotic cells, particularly in the plasma membrane. It is the major substrate for receptor-stimulated phosphoinositidase C, with the consequent formation of inositol 1,4,5-triphosphate and diacylglycerol, and probably also for receptor-stimulated inositol phospholipid 3-kinase. (Kendrew, The Encyclopedia of Molecular Biology, 1994)Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3.Brain: 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.Sirtuins: A homologous family of regulatory enzymes that are structurally related to the protein silent mating type information regulator 2 (Sir2) found in Saccharomyces cerevisiae. Sirtuins contain a central catalytic core region which binds NAD. Several of the sirtuins utilize NAD to deacetylate proteins such as HISTONES and are categorized as GROUP III HISTONE DEACETYLASES. Several other sirtuin members utilize NAD to transfer ADP-RIBOSE to proteins and are categorized as MONO ADP-RIBOSE TRANSFERASES, while a third group of sirtuins appears to have both deacetylase and ADP ribose transferase activities.Plant Proteins: Proteins found in plants (flowers, herbs, shrubs, trees, etc.). The concept does not include proteins found in vegetables for which VEGETABLE PROTEINS is available.Rats, Wistar: A strain of albino rat developed at the Wistar Institute that has spread widely at other institutions. This has markedly diluted the original strain.Class I Phosphatidylinositol 3-Kinases: A phosphatidylinositol 3-kinase subclass that includes enzymes with a specificity for 1-phosphatidylinositol, 1-phosphatidylinositol 4-phosphate, and 1-phosphatidylinositol 4,5-bisphosphate. Members of this enzyme subclass are activated by cell surface receptors and occur as heterodimers of enzymatic and regulatory subunits.Egtazic Acid: A chelating agent relatively more specific for calcium and less toxic than EDETIC ACID.MAP Kinase Kinase 4: A mitogen-activated protein kinase kinase with specificity for JNK MITOGEN-ACTIVATED PROTEIN KINASES; P38 MITOGEN-ACTIVATED PROTEIN KINASES and the RETINOID X RECEPTORS. It takes part in a SIGNAL TRANSDUCTION pathway that is activated in response to cellular stress.Glycogen Synthase Kinase 3: 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.Neurons: 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.Staurosporine: An indolocarbazole that is a potent PROTEIN KINASE C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)Sirtuin 1: A sirtuin family member found primarily in the CELL NUCLEUS. It is an NAD-dependent deacetylase with specificity towards HISTONES and a variety of proteins involved in gene regulation.Phorbol Esters: Tumor-promoting compounds obtained from CROTON OIL (Croton tiglium). Some of these are used in cell biological experiments as activators of protein kinase C.DNA-Binding Proteins: 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.Casein Kinases: 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.Tyrosine: A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin.MaleimidesHeLa Cells: 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.Indoles: 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.Magnesium: A metallic element that has the atomic symbol Mg, atomic number 12, and atomic weight 24.31. It is important for the activity of many enzymes, especially those involved in OXIDATIVE PHOSPHORYLATION.Inositol Phosphates: Phosphoric acid esters of inositol. They include mono- and polyphosphoric acid esters, with the exception of inositol hexaphosphate which is PHYTIC ACID.Cell Nucleus: 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)Cyclin-Dependent Kinases: 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.Muscle, Smooth, Vascular: The nonstriated involuntary muscle tissue of blood vessels.3T3 Cells: 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.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.Cell Survival: 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.Flavonoids: A group of phenyl benzopyrans named for having structures like FLAVONES.Mice, Inbred C57BLFibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.TOR Serine-Threonine Kinases: 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.RNA, Small Interfering: 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.Arabidopsis Proteins: Proteins that originate from plants species belonging to the genus ARABIDOPSIS. The most intensely studied species of Arabidopsis, Arabidopsis thaliana, is commonly used in laboratory experiments.Mice, Knockout: 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.Diacylglycerol Kinase: An enzyme of the transferase class that uses ATP to catalyze the phosphorylation of diacylglycerol to a phosphatidate. EC 2.7.1.107.Precipitin Tests: 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.Receptor Protein-Tyrosine Kinases: A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity.Down-Regulation: 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.Saccharomyces cerevisiae: A species of the genus SACCHAROMYCES, family Saccharomycetaceae, order Saccharomycetales, known as "baker's" or "brewer's" yeast. The dried form is used as a dietary supplement.Saccharomyces cerevisiae Proteins: Proteins obtained from the species SACCHAROMYCES CEREVISIAE. The function of specific proteins from this organism are the subject of intense scientific interest and have been used to derive basic understanding of the functioning similar proteins in higher eukaryotes.Cell Cycle: The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.Creatine Kinase: 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.DNA-Activated Protein Kinase: A serine-threonine protein kinase that, when activated by DNA, phosphorylates several DNA-binding protein substrates including the TUMOR SUPPRESSOR PROTEIN P53 and a variety of TRANSCRIPTION FACTORS.Swine: Any of various animals that constitute the family Suidae and comprise stout-bodied, short-legged omnivorous mammals with thick skin, usually covered with coarse bristles, a rather long mobile snout, and small tail. Included are the genera Babyrousa, Phacochoerus (wart hogs), and Sus, the latter containing the domestic pig (see SUS SCROFA).Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.Nuclear Proteins: 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.Threonine: 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.Hippocampus: A curved elevation of GRAY MATTER extending the entire length of the floor of the TEMPORAL HORN of the LATERAL VENTRICLE (see also TEMPORAL LOBE). The hippocampus proper, subiculum, and DENTATE GYRUS constitute the hippocampal formation. Sometimes authors include the ENTORHINAL CORTEX in the hippocampal formation.Arabidopsis: A plant genus of the family BRASSICACEAE that contains ARABIDOPSIS PROTEINS and MADS DOMAIN PROTEINS. The species A. thaliana is used for experiments in classical plant genetics as well as molecular genetic studies in plant physiology, biochemistry, and development.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.Up-Regulation: 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.rho-Associated Kinases: A group of intracellular-signaling serine threonine kinases that bind to RHO GTP-BINDING PROTEINS. They were originally found to mediate the effects of rhoA GTP-BINDING PROTEIN on the formation of STRESS FIBERS and FOCAL ADHESIONS. Rho-associated kinases have specificity for a variety of substrates including MYOSIN-LIGHT-CHAIN PHOSPHATASE and LIM KINASES.Pyridines: Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.DNA Primers: 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.Cell Cycle Proteins: Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.Pyruvate Kinase: 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.Adaptor Proteins, Signal Transducing: 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 enzymesImidazoles: Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).Alkaloids: Organic nitrogenous bases. Many alkaloids of medical importance occur in the animal and vegetable kingdoms, and some have been synthesized. (Grant & Hackh's Chemical Dictionary, 5th ed)Subcellular Fractions: Components of a cell produced by various separation techniques which, though they disrupt the delicate anatomy of a cell, preserve the structure and physiology of its functioning constituents for biochemical and ultrastructural analysis. (From Alberts et al., Molecular Biology of the Cell, 2d ed, p163)Phosphoserine: The phosphoric acid ester of serine.Cell Proliferation: All of the processes involved in increasing CELL NUMBER including CELL DIVISION.Protein Isoforms: Different forms of a protein that may be produced from different GENES, or from the same gene by ALTERNATIVE SPLICING.Second Messenger Systems: Systems in which an intracellular signal is generated in response to an intercellular primary messenger such as a hormone or neurotransmitter. They are intermediate signals in cellular processes such as metabolism, secretion, contraction, phototransduction, and cell growth. Examples of second messenger systems are the adenyl cyclase-cyclic AMP system, the phosphatidylinositol diphosphate-inositol triphosphate system, and the cyclic GMP system.Biological Transport: The movement of materials (including biochemical substances and drugs) through a biological system at the cellular level. The transport can be across cell membranes and epithelial layers. It also can occur within intracellular compartments and extracellular compartments.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.DNA, Complementary: Single-stranded complementary DNA synthesized from an RNA template by the action of RNA-dependent DNA polymerase. cDNA (i.e., complementary DNA, not circular DNA, not C-DNA) is used in a variety of molecular cloning experiments as well as serving as a specific hybridization probe.Cell Differentiation: Progressive restriction of the developmental potential and increasing specialization of function that leads to the formation of specialized cells, tissues, and organs.Ribosomal Protein S6 Kinases, 90-kDa: A family of ribosomal protein S6 kinases that are structurally distinguished from RIBOSOMAL PROTEIN S6 KINASES, 70-KDA by their apparent molecular size and the fact they contain two functional kinase domains. Although considered RIBOSOMAL PROTEIN S6 KINASES, members of this family are activated via the MAP KINASE SIGNALING SYSTEM and have been shown to act on a diverse array of substrates that are involved in cellular regulation such as RIBOSOMAL PROTEIN S6 and CAMP RESPONSE ELEMENT-BINDING PROTEIN.Class Ia Phosphatidylinositol 3-Kinase: A phosphatidylinositol 3-kinase subclass that includes enzymes formed through the heterodimerization of a p110 catalytic and a p85, p55, or p50 regulatory subunit. This subclass of enzymes is a downstream target of TYROSINE KINASE RECEPTORS and G PROTEIN-COUPLED RECEPTORS.Protein Processing, Post-Translational: 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.I-kappa B Kinase: A protein serine-threonine kinase that catalyzes the PHOSPHORYLATION of I KAPPA B PROTEINS. This enzyme also activates the transcription factor NF-KAPPA B and is composed of alpha and beta catalytic subunits, which are protein kinases and gamma, a regulatory subunit.Insulin: 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).Phosphatidylinositol 3-Kinase: A phosphatidylinositol 3-kinase that catalyzes the conversion of 1-phosphatidylinositol into 1-phosphatidylinositol 3-phosphate.
Intracellular signalling: PDK1--a kinase at the hub of things. (1/431)
Phosphoinositide-dependent kinase 1 (PDK1) is at the hub of many signalling pathways, activating PKB and PKC isoenzymes, as well as p70 S6 kinase and perhaps PKA. PDK1 action is determined by colocalization with substrate and by target site availability, features that may enable it to operate in both resting and stimulated cells. (+info)Functional counterparts of mammalian protein kinases PDK1 and SGK in budding yeast. (2/431)
BACKGROUND: In animal cells, recruitment of phosphatidylinositol 3-kinase by growth factor receptors generates 3-phosphoinositides, which stimulate 3-phosphoinositide-dependent protein kinase-1 (PDK1). Activated PDK1 then phosphorylates and activates downstream protein kinases, including protein kinase B (PKB)/c-Akt, p70 S6 kinase, PKC isoforms, and serum- and glucocorticoid-inducible kinase (SGK), thereby eliciting physiological responses. RESULTS: We found that two previously uncharacterised genes of Saccharomyces cerevisiae, which we term PKH1 and PKH2, encode protein kinases with catalytic domains closely resembling those of human and Drosophila PDK1. Both Pkh1 and Pkh2 were essential for cell viability. Expression of human PDK1 in otherwise inviable pkh1Delta pkh2Delta cells permitted growth. In addition, the yeast YPK1 and YKR2 genes were found to encode protein kinases each with a catalytic domain closely resembling that of SGK; both Ypk1 and Ykr2 were also essential for viability. Otherwise inviable ypk1Delta ykr2Delta cells were fully rescued by expression of rat SGK, but not mouse PKB or rat p70 S6 kinase. Purified Pkh1 activated mammalian SGK and PKBalpha in vitro by phosphorylating the same residue as PDK1. Pkh1 activated purified Ypk1 by phosphorylating the equivalent residue (Thr504) and was required for maximal Ypk1 phosphorylation in vivo. Unlike PKB, activation of Ypk1 and SGK by Pkh1 did not require phosphatidylinositol 3,4,5-trisphosphate, consistent with the absence of pleckstrin homology domains in these proteins. The phosphorylation consensus sequence for Ypk1 was similar to that for PKBalpha and SGK. CONCLUSIONS: Pkh1 and Pkh2 function similarly to PDK1, and Ypk1 and Ykr2 to SGK. As in animal cells, these two groups of yeast kinases constitute two tiers of a signalling cascade required for yeast cell growth. (+info)Primary structure, tissue distribution, and expression of mouse phosphoinositide-dependent protein kinase-1, a protein kinase that phosphorylates and activates protein kinase Czeta. (3/431)
Phosphoinositide-dependent protein kinase-1 (PDK1) is a recently identified serine/threonine kinase that phosphorylates and activates Akt and p70(S6K), two downstream kinases of phosphatidylinositol 3-kinase. To further study the potential role of PDK1, we have screened a mouse liver cDNA library and identified a cDNA encoding the enzyme. The predicted mouse PDK1 (mPDK1) protein contained 559 amino acids and a COOH-terminal pleckstrin homology domain. A 7-kilobase mPDK1 mRNA was broadly expressed in mouse tissues and in embryonic cells. In the testis, a high level expression of a tissue-specific 2-kilobase transcript was also detected. Anti-mPDK1 antibody recognized multiple proteins in mouse tissues with molecular masses ranging from 60 to 180 kDa. mPDK1 phosphorylated the conserved threonine residue (Thr402) in the activation loop of protein kinase C-zeta and activated the enzyme in vitro and in cells. Our findings suggest that there may be different isoforms of mPDK1 and that the protein is an upstream kinase that activates divergent pathways downstream of phosphatidylinositol 3-kinase. (+info)p70 S6 kinase is regulated by protein kinase Czeta and participates in a phosphoinositide 3-kinase-regulated signalling complex. (4/431)
p70 S6 kinase (p70S6K) is an important regulator of cell proliferation. Its activation by growth factor requires phosphorylation by various inputs on multiple sites. Data accumulated thus far support a model whereby p70S6K activation requires sequential phosphorylations at proline-directed residues in the putative autoinhibitory pseudosubstrate domain, as well as threonine 389. Threonine 229, a site in the catalytic loop is phosphorylated by phosphoinositide-dependent kinase 1 (PDK-1). Experimental evidence suggests that p70S6K activation requires a phosphoinositide 3-kinase (PI3-K)-dependent signal(s). However, the intermediates between PI3-K and p70S6K remain unclear. Here, we have identified PI3-K-regulated atypical protein kinase C (PKC) isoform PKCzeta as an upstream regulator of p70S6K. In coexpression experiments, we found that a kinase-inactive PKCzeta mutant antagonized activation of p70S6K by epidermal growth factor, PDK-1, and activated Cdc42 and PI3-K. While overexpression of a constitutively active PKCzeta mutant (myristoylated PKCzeta [myr-PKCzeta]) only modestly activated p70S6K, this mutant cooperated with PDK-1 activation of p70S6K. PDK-1-induced activation of a C-terminal truncation mutant of p70S6K was also enhanced by myr-PKCzeta. Moreover, we have found that p70S6K can associate with both PDK-1 and PKCzeta in vivo in a growth factor-independent manner, while PDK-1 and PKCzeta can also associate with each other, suggesting the existence of a multimeric PI3-K signalling complex. This work provides evidence for a link between a phorbol ester-insensitive PKC isoform and p70S6K. The existence of a PI3-K-dependent signalling complex may enable efficient activation of p70S6K in cells. (+info)Activation of serum- and glucocorticoid-regulated protein kinase by agonists that activate phosphatidylinositide 3-kinase is mediated by 3-phosphoinositide-dependent protein kinase-1 (PDK1) and PDK2. (5/431)
The PtdIns(3,4,5)P3-dependent activation of protein kinase B (PKB) by 3-phosphoinositide-dependent protein kinases-1 and -2 (PDK1 and PDK2 respectively) is a key event in mediating the effects of signals that activate PtdIns 3-kinase. The catalytic domain of serum- and glucocorticoid-regulated protein kinase (SGK) is 54% identical with that of PKB and, although lacking the PtdIns(3,4, 5)P3-binding pleckstrin-homology domain, SGK retains the residues that are phosphorylated by PDK1 and PDK2, which are Thr256 and Ser422 in SGK. Here we show that PDK1 activates SGK in vitro by phosphorylating Thr256. We also show that, in response to insulin-like growth factor-1 (IGF-1) or hydrogen peroxide, transfected SGK is activated in 293 cells via a PtdIns 3-kinase-dependent pathway that involves the phosphorylation of Thr256 and Ser422. The activation of SGK by PDK1 in vitro is unaffected by PtdIns(3,4,5)P3, abolished by the mutation of Ser422 to Ala, and greatly potentiated by mutation of Ser422 to Asp (although this mutation does not activate SGK itself). Consistent with these findings, the Ser422Asp mutant of SGK is activated by phosphorylation (probably at Thr256) in unstimulated 293 cells, and activation is unaffected by inhibitors of PtdIns 3-kinase. Our results are consistent with a model in which activation of SGK by IGF-1 or hydrogen peroxide is initiated by a PtdIns(3,4, 5)P3-dependent activation of PDK2, which phosphorylates Ser422. This is followed by the PtdIns(3,4,5)P3-independent phosphorylation at Thr256 that activates SGK, and is catalysed by PDK1. Like PKB, SGK preferentially phosphorylates serine and threonine residues that lie in Arg-Xaa-Arg-Xaa-Xaa-Ser/Thr motifs, and SGK and PKB inactivate glycogen synthase kinase-3 similarly in vitro and in co-transfection experiments. These findings raise the possibility that some physiological roles ascribed to PKB on the basis of the overexpression of constitutively active PKB mutants might be mediated by SGK. (+info)The Croonian Lecture 1998. Identification of a protein kinase cascade of major importance in insulin signal transduction. (6/431)
Diabetes affects 3% of the European population and 140 million people worldwide, and is largely a disease of insulin resistance in which the tissues fail to respond to this hormone. This emphasizes the importance of understanding how insulin signals to the cell's interior. We have recently dissected a protein kinase cascade that is triggered by the formation of the insulin 'second messenger' phosphatidylinositide (3,4,5) trisphosphate (PtdIns (3,4,5)P3) and which appears to mediate many of the metabolic actions of this hormone. The first enzyme in the cascade is termed 3-phosphoinositide-dependent protein kinase-1 (PDK1), because it only activates protein kinase B (PKB), the next enzyme in the pathway, in the presence of PtdIns (3,4,5)P3. PKB then inactivates glycogen synthase kinase-3 (GSK3). PDK1, PKB and GSK3 regulate many physiological events by phosphorylating a variety of intracellular proteins. In addition, PKB plays an important role in mediating protection against apoptosis by survival factors, such as insulin-like growth factor-1. (+info)PDK1 acquires PDK2 activity in the presence of a synthetic peptide derived from the carboxyl terminus of PRK2. (7/431)
BACKGROUND: Protein kinase B (PKB) is activated by phosphorylation of Thr308 and of Ser473. Thr308 is phosphorylated by the 3-phosphoinositide-dependent protein kinase-1 (PDK1) but the identity of the kinase that phosphorylates Ser473 (provisionally termed PDK2) is unknown. RESULTS: The kinase domain of PDK1 interacts with a region of protein kinase C-related kinase-2 (PRK2), termed the PDK1-interacting fragment (PIF). PIF is situated carboxy-terminal to the kinase domain of PRK2, and contains a consensus motif for phosphorylation by PDK2 similar to that found in PKBalpha, except that the residue equivalent to Ser473 is aspartic acid. Mutation of any of the conserved residues in the PDK2 motif of PIF prevented interaction of PIF with PDK1. Remarkably, interaction of PDK1 with PIF, or with a synthetic peptide encompassing the PDK2 consensus sequence of PIF, converted PDK1 from an enzyme that could phosphorylate only Thr308 of PKBalpha to one that phosphorylates both Thr308 and Ser473 of PKBalpha in a manner dependent on phosphatidylinositol (3,4,5) trisphosphate (PtdIns(3,4,5)P3). Furthermore, the interaction of PIF with PDK1 converted the PDK1 from a form that is not directly activated by PtdIns(3,4,5)P3 to a form that is activated threefold by PtdIns(3,4,5)P3. We have partially purified a kinase from brain extract that phosphorylates Ser473 of PKBalpha in a PtdIns(3,4,5)P3-dependent manner and that is immunoprecipitated with PDK1 antibodies. CONCLUSIONS: PDK1 and PDK2 might be the same enzyme, the substrate specificity and activity of PDK1 being regulated through its interaction with another protein(s). PRK2 is a probable substrate for PDK1. (+info)Mutational analysis of the coding regions of the genes encoding protein kinase B-alpha and -beta, phosphoinositide-dependent protein kinase-1, phosphatase targeting to glycogen, protein phosphatase inhibitor-1, and glycogenin: lessons from a search for genetic variability of the insulin-stimulated glycogen synthesis pathway of skeletal muscle in NIDDM patients. (8/431)
The finding of a reduced insulin-stimulated glucose uptake and glycogen synthesis in the skeletal muscle of glucose-tolerant first-degree relatives of patients with NIDDM, as well as in cultured fibroblasts and skeletal muscle cells isolated from NIDDM patients, has been interpreted as evidence for a genetic involvement in the disease. The mode of inheritance of the common forms of NIDDM is as yet unclear, but the prevailing hypothesis supports a polygenic model. In the present study, we tested the hypothesis that the putative inheritable defects of insulin-stimulated muscle glycogen synthesis might be caused by genetic variability in the genes encoding proteins shown by biochemical evidence to be involved in insulin-stimulated glycogen synthesis in skeletal muscle. In 70 insulin-resistant Danish NIDDM patients, mutational analysis by reverse transcription-polymerase chain reaction-single strand conformation polymorphism-heteroduplex analysis was performed on genomic DNA or skeletal muscle-derived cDNAs encoding glycogenin, protein phosphatase inhibitor-1, phophatase targeting to glycogen, protein kinase B-alpha and -beta, and the phosphoinositide-dependent protein kinase-1. Although a number of silent variants were identified in some of the examined genes, we found no evidence for the hypothesis that the defective insulin-stimulated glycogen synthesis in skeletal muscle in NIDDM is caused by structural changes in the genes encoding the known components of the insulin-sensitive glycogen synthesis pathway of skeletal muscle. (+info)
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GRB14"The adapter protein ZIP binds Grb14 and regulates its inhibitory action on insulin signaling by recruiting protein kinase Czeta ... This protein likely has an inhibitory effect on receptor tyrosine kinase signaling and, in particular, on insulin receptor ... Growth factor receptor-bound protein 14 is a protein that in humans is encoded by the GRB14 gene. The product of this gene ... belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and ...
These two paralogue proteins self-assemble in higher order structure helices and bind preferentially to phosphoinositide- ... BAR) Bin-Amphiphysin-RVS Slm1 Phosphoinositide PI4,5P(2) binding protein, forms a complex with Slm2p; acts downstream of Mss4p ... These are large protein complexes composed primarily of subunits of two Bin-Amphiphysin-RVS (BAR) domain containing proteins ... phosphorylated by the TORC2 complex Slm2 Phosphoinositide PI4,5P(2) binding protein, forms a complex with Slm1p; acts ...
... phosphoinositide-dependent protein kinase-1 and regulates glucose-induced biological responses in pancreatic beta-cells". ... miR-375 has been shown to target the MTPN gene, which encodes the myotrophin protein, that regulates hormone release and ... protein expression". Int J Clin Exp Pathol. 3 (3): 254-64. PMC 2836503 . PMID 20224724. El Ouaamari A, Baroukh N, Martens GA, ... 394 (3): 623-7. doi:10.1016/j.bbrc.2010.03.036. PMID 20226166. Poy MN, Hausser J, Trajkovski M, Braun M, Collins S, Rorsman P, ...
Hetz CA, Hunn M, Rojas P, Torres V, Leyton L, Quest AF (December 2002). "Caspase-dependent initiation of apoptosis and necrosis ... Snider AJ, Orr Gandy KA, Obeid LM (June 2010). "Sphingosine kinase: Role in regulation of bioactive sphingolipid mediators in ... These sphingolipid-based microdomains, or "lipid rafts" were originally proposed to sort membrane proteins along the cellular ... It may be phosphorylated by ceramide kinase to form ceramide-1-phosphate. Alternatively, it may be glycosylated by ...
"Rab2 interacts directly with atypical protein kinase C (aPKC) iota/lambda and inhibits aPKCiota/lambda-dependent glyceraldehyde ... protein kinase C inhibitor bisindolyl maleimide 2 binds with reversed orientations to different conformations of protein kinase ... a novel protein that specifically interacts with the zinc finger domain of the atypical protein kinase C isotype lambda/iota ... "Crystal structure of the catalytic subunit of cyclic adenosine monophosphate-dependent protein kinase". Science. 253 (5018): ...
Phosphoinositide-dependent kinase-1, EZR, PODXL, Cystic fibrosis transmembrane conductance regulator and PLCB3. Solute carrier ... also known as tyrosine kinase activator protein 1 (TKA-1) or SRY-interacting protein 1 (SIP-1) is a protein that in humans is ... "NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ... "NHE3 kinase A regulatory protein E3KARP binds the epithelial brush border Na+/H+ exchanger NHE3 and the cytoskeletal protein ...
OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proc. ... 1998). "Phosphoinositide-3- ... "Eosinophil granule cationic proteins: major basic protein is ... "Complex of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein. Disulfide structure and ... 1994). "Localization of pregnancy-associated plasma protein-A and colocalization of pregnancy-associated plasma protein-A ...
... has been shown to interact with: AKAP9, Actinin, alpha 1, CCDC85B, NEFL, NEUROD2 Phosphoinositide-dependent ... This kinase is activated by Rho family of small G proteins and may mediate the Rho-dependent signaling pathway. This kinase can ... "A novel protein kinase with leucine zipper-like sequences: its catalytic domain is highly homologous to that of protein kinase ... Serine/threonine-protein kinase N1 is an enzyme that in humans is encoded by the PKN1 gene. The protein encoded by this gene ...
... through a protein kinase C-dependent mechanism". The Biochemical Journal. 466 (2): 379-90. doi:10.1042/BJ20140881. PMID ... membrane-bound receptor for activated protein kinase C proteins). The protein kinase C enzymes are known for their long-term ... Protein kinase C, commonly abbreviated to PKC (EC 2.7.11.13), is a family of protein kinase enzymes that are involved in ... The consensus sequence of protein kinase C enzymes is similar to that of protein kinase A, since it contains basic amino acids ...
The protein encoded by this gene is a member of the AKT subfamily of serine/threonine protein kinases. AKT kinases are known to ... AKT-dependent survival pathways in Kaposi's sarcoma cells". J. Biol. Chem. 277 (28): 25195-202. doi:10.1074/jbc.M200921200. ... protein kinase B, gamma)". Hodgkinson CP, Sale EM, Sale GJ (2002). "Characterization of PDK2 activity against protein kinase B ... Walker KS, Deak M, Paterson A, Hudson K, Cohen P, Alessi DR (1998). "Activation of protein kinase B beta and gamma isoforms by ...
This protein kinase is calcium-independent and phospholipid-dependent. It is not activated by phorbolesters or diacylglycerol. ... Phosphoinositide-dependent kinase-1, SMG1 (gene), Sequestosome 1, KRAS. Vimentin GRCh38: Ensembl release 89: ENSG00000163558 - ... This gene encodes a member of the protein kinase C (PKC) family of serine/threonine protein kinases. The PKC family comprises ... Lim YP, Low BC, Lim J, Wong ES, Guy GR (Jul 1999). "Association of atypical protein kinase C isotypes with the docker protein ...
... has been shown to interact with: AKT1, PKN2, PRKACA, PRKCD, PRKCI, Protein kinase Mζ, ... "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and ... "Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/ ... "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science. 281 (5385): 2042-5 ...
"Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science. 281 (5385): 2042-5 ... "Protein kinase M zeta synthesis from a brain mRNA encoding an independent protein kinase C zeta catalytic domain. Implications ... Protein kinase C, zeta (PKCζ), also known as PRKCZ, is a protein that in humans is encoded by the PRKCZ gene. The PRKCZ gene ... of the Caenorhabditis elegans UNC-76 protein involved in axonal outgrowth is a protein kinase C zeta-interacting protein". J. ...
The encoded protein is a general protein kinase capable of phosphorylating several known proteins. The gene was shown to be ... OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proc. ... Delcommenne M, Tan C, Gray V, Rue L, Woodgett J, Dedhar S (1998). "Phosphoinositide-3- ... "Inhibition of insulin-induced activation of Akt by a kinase-deficient mutant of the epsilon isozyme of protein kinase C". J. ...
... protein kinase B)/glycogen synthase kinase-3 signaling pathway via phosphatidylinositol 3-kinase". Journal of Immunology. 163 ( ... Additionally, inhibition of PDK2 subsequently inhibits HIF1A in cancer cells by both a prolyl-hydroxylase (PHD)-dependent ... "Structure of pyruvate dehydrogenase kinase. Novel folding pattern for a serine protein kinase". The Journal of Biological ... PDK2 is an isozyme of pyruvate dehydrogenase kinase. The protein encoded by the PDK2 gene has two sites, an active site and an ...
NIMA-related kinases (NEKs) are a group of protein kinases that are homologous to NIMA. Evidence suggests that NEKs perform ... "Identification and characterization of Nek6 protein kinase, a potential human homolog of NIMA histone H3 kinase". Biochem. ... Serine/threonine-protein kinase Nek6 is an enzyme that in humans is encoded by the NEK6 gene. The Aspergillus nidulans 'never ... It is a protein kinase which plays an important role in mitotic cell cycle progression. Required for chromosome segregation at ...
Lizcano JM, Morrice N, Cohen P (2001). "Regulation of BAD by cAMP-dependent protein kinase is mediated via phosphorylation of a ... a new MAP kinase-activated protein kinase, isolated by a novel expression screening method for identifying protein kinase ... This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine and threonine kinases. This kinase contains 2 non- ... Ribosomal protein S6 kinase alpha-2 is an enzyme that in humans is encoded by the RPS6KA2 gene. ...
5-trisphosphate-dependent activation of protein kinase B". Science. 279 (5351): 710-4. doi:10.1126/science.279.5351.710. PMID ... "Carboxyl-terminal region conserved among phosphoinositide-kinase-related kinases is indispensable for mTOR function in vivo and ... and protein kinase C α (PKCα). mTORC2 also phosphorylates the serine/threonine protein kinase Akt/PKB on serine residue Ser473 ... "Functional interaction between RAFT1/FRAP/mTOR and protein kinase cdelta in the regulation of cap-dependent initiation of ...
OH kinase-dependent regulation of glycogen synthase kinase 3 and protein kinase B/AKT by the integrin-linked kinase". Proc. ... 1998). "Phosphoinositide-3- ... "Eosinophil granule cationic proteins: major basic protein is ... Major basic protein has been shown to interact with Pregnancy-associated plasma protein A. arylsulfatase GRCh38: Ensembl ... Structurally the major basic protein (MBP) is similar to lectins (sugar-binding proteins), and has a fold similar to that seen ...
"Regulation of cell adhesion and anchorage-dependent growth by a new beta 1-integrin-linked protein kinase". Nature. 379 (6560 ... Phosphoinositide binding motif and extreme N-terminus of kinase catalytic domain. Integrins lack enzymatic activity and depend ... "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and ... "Inhibition of insulin-induced activation of Akt by a kinase-deficient mutant of the epsilon isozyme of protein kinase C". The ...
They - in parallel with Dario Alessi - identified phosphoinositide-dependent kinase-1 as the PtdIns(3,4,5)P3-activated link ... 5-Trisphosphate-Dependent Activation of Protein Kinase B". Science. 279: 710-714. doi:10.1126/science.279.5351.710. PMID ... "Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4, ... 5-trisphosphate in the activation of protein kinase B". Science ... between PI3K-1 activation and protein kinase B activation, a key pathway through which PtdIns(3,4,5)P3 formation regulates cell ...
They - in parallel with Dario Alessi - identified phosphoinositide-dependent kinase-1 as the PtdIns(3,4,5)P3-activated link ... 5-Trisphosphate-Dependent Activation of Protein Kinase B. Science 279, 710-714 Phill Hawkins' group at the Babraham Institute. ... Protein Kinase B Kinases That Mediate Phosphatidylinositol 3,4, ... 5-trisphosphate in the Activation of Protein Kinase B. Science ... between PI3K-1 activation and protein kinase B activation, a key pathway through which PtdIns(3,4,5)P3 formation regulates cell ...
... phosphoinositide dependent kinase 1 (PDPK1 at threonine 308) and the mammalian target of rapamycin complex 2 (mTORC2 at serine ... including integrin-linked kinase (ILK) and mitogen-activated protein kinase-activated protein kinase-2 (MAPKAPK2) can also ... Protein kinase B (PKB), also known as Akt, is a serine/threonine-specific protein kinase that plays a key role in multiple ... Yang ZZ, Tschopp O, Baudry A, Dümmler B, Hynx D, Hemmings BA (April 2004). "Physiological functions of protein kinase B/Akt". ...
... and the lipid dependent protein kinase B (PKB) signaling pathway increases the survival of lymphocytes and other immune cells ... Phosphoinositide 3-kinase (PI3K) and the GTPase RAC are responsible of the lymphocytes migration and their interactions with ... All the intracellular functions occur via the interaction with Gαi and Gαo: these two proteins recruit other proteins for ... mitogen-activated protein kinase pathway". J. Biol. Chem. 271 (19): 11272-9. doi:10.1074/jbc.271.19.11272. PMID 8626678. " ...
"Tobacco components stimulate Akt-dependent proliferation and NFkappaB-dependent survival in lung cancer cells". Carcinogenesis ... The phosphoinositide 3-kinase (PI3K/Akt) pathway is also an important contributor to NNK-induced cellular transformations and ... The ERK1/2 and Akt pathways show consequential changes in levels of protein expression as a result of NNK-activation in the ... NNK activates µ en m-calpain kinase which induce lung metastasis via the ERK1/2 pathway. This pathway upregulate cellular ...
P binding protein of the WIPI (WD-repeat protein interacting with phosphoinositides) protein family, was recently shown to ... E. Y. Chan, 'Regulation and Function of Uncoordinated-51 Like Kinase Proteins', Antioxid Redox Signal, 17 (2012), 775-85 ... This is directly related to the growth of cancer cells in a dose-dependent manner as well.[84][87] This data supports the ... Without efficient autophagy, neurons gather ubiquitinated protein aggregates and degrade. Ubiquitinated proteins are proteins ...
... p65 protein expression in a dose-dependent manner (Figure 4B). Note that NAC had no effect on p50 protein (Figure 4B). ... protein kinase-1 regulates proliferation and survival of cancer cells with an activated mitogen-activated protein kinase ... As shown in Figure 2A-B, NAC induced PPARα protein expression in a dose- and time-dependent manner with a maximal induction ... Cells exposed to NAC resulted in significant decrease in PDK1 protein expression in a dose- and time-dependent manner with ...
P3-dependent protein kinase-1 (PDK1). None of the inositol phospholipids tested activated or inhibited PKBalpha or induced its ... Protein kinase B (PKB), also known as c-Akt, is activated rapidly when mammalian cells are stimulated with insulin and growth ... CONLCUSIONS: PDK1 is likely to be one of the protein kinases that mediate the activation of PKB by insulin and growth factors. ... We have purified 500 000-fold from rabbit skeletal muscle extracts a protein kinase which phosphorylates PKBalpha at Thr308 and ...
The activation of protein kinase B (PKB, also known as c-Akt) is stimulated by insulin or growth factors and results from its ... We recently identified a protein kinase, termed PDK1, that phosphorylates PKB at Thr308 only in the presence of lipid vesicles ... Human PDK1 is homologous to the Drosophila protein kinase DSTPK61, which has been implicated in the regulation of sex ... PKB and PKC subfamily of protein kinases and a carboxy-terminal pleckstrin homology (PH) domain. The PDK1 gene is located on ...
Regulation of Leukocyte Degranulation by cGMP-Dependent Protein Kinase and Phosphoinositide 3-Kinase: Potential Roles in...Activation of cGMP-dependent protein kinase by protein kinase C. J. Biol. Chem. 278: 16706-16712. ... Nitric oxide activation of p38 mitogen-activated protein kinase in 293T fibroblasts requires cGMP-dependent protein kinase. J. ... K-252 compounds, novel and potent inhibitors of protein kinase C and cyclic nucleotide-dependent protein kinases. Biochem. ... SNAP receptor protein; t-SNARE, target membrane SNARE; PLC, phospholipase C; PKC, protein kinase C; PKG, cGMP-dependent protein ...
... kinase (e.g., LY294002; Ref. 27 ), protein kinase C (staurosporine; Ref. 28 ), cyclin-dependent kinases (29) , and vascular ... Tsichlis PN AKT/PKB and other D3 phosphoinositide-regulated kinases: kinase activation by phosphoinositide-dependent ... phosphoinositide-dependent protein kinase-1. J Biol Chem, 275: 40400-6, 2000. ... phosphoinositide-dependent kinase-1 (PDK-1) in PI 3- kinase signaling. Front Biosci, 7: d886-902, 2002. ...
Activation of protein kinase B β and γ isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in ... comparison with protein kinase B α. Kay S. WALKER, Maria DEAK, Andrew PATERSON, Kevin HUDSON, Philip COHEN, Dario R. ALESSI ... Activation of protein kinase B β and γ isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in ... Activation of protein kinase B β and γ isoforms by insulin in vivo and by 3-phosphoinositide-dependent protein kinase-1 in ...
3-phosphoinositide dependent protein kinase 1 | PDK1 family | IUPHAR Guide to IMMUNOPHARMACOLOGY3-phosphoinositide dependent protein kinase 1 - PDK1 family. Detailed annotation on the structure, function, physiology, ... Phosphoinositide-dependent protein kinase 1 (PDK1) mediates potent inhibitory effects on eosinophils. Eur. J. Immunol., 45 (5 ... PkB kinase , protein kinase B kinase , 3-phosphoinositide dependent protein kinase-1 ... 2010) Molecular pharmacology and antitumor activity of PHT-427, a novel Akt/phosphatidylinositide-dependent protein kinase 1 ...
PDK1 mediates its effect in part by MT1-MMP induction, which in turn activates MMP-2 and modulates the ECM proteins decorin and ... We now present evidence showing that PDK1-expressing cells exhibit enhanced anchorage-dependent and -independent cell growth ... Filippa N, Sable CL, Hemmings BA, Van Obberghen E: Effect of phosphoinositide-dependent kinase 1 on protein kinase B ... Dutil EM, Toker A, Newton AC: Regulation of conventional protein kinase C isozymes by phosphoinositide-dependent kinase 1 (PDK- ...
Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol DerivateD. E. Heppner and A. van der Vliet, "Redox-dependent regulation of epidermal growth factor receptor signaling," Redox Biology, ... MI-1 was synthesized as protein kinases inhibitor [8]. It was tested on 32 protein kinases for determination of inhibitory ... Anti-Inflammatory Effects of Protein Kinase Inhibitor Pyrrol Derivate. Halyna M. Kuznietsova, Maryna S. Yena, Iryna P. Kotlyar ... Protein kinase inhibitor pyrrol derivate 1-(4-Cl-benzyl)-3-Cl-4-(CF3-fenylamino)-1Н-pyrrol-2,5-dione (MI-1) (Figure 1) has been ...
Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life...... dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic ... Phosphoinositide metabolism links cGMP-dependent protein kinase G to essential Ca²⁺ signals at key decision points in the life ... dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca²⁺ required for gliding motility. We find that the ... dependent protein kinases. Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic ...
Specificity analysis with a panel of 29 protein kinases reveals that these bisindolyl maleimide inhibitors also inhibit PDK1, a ... nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and ... nanomolar protein kinase C inhibitors. LY333531, a PKCbeta-specific inhibitor, is in clinical trials against diabetes and ... Structure of human PDK1 kinase domain in complex with BIM-3. *DOI: 10.2210/pdb1UU9/pdb ...
Sequence domains: Protein kinase domain Structure domains: * Phosphorylase Kinase; domain 1 * Transferase(Phosphotransferase) ... Protein kinase, ATP binding site * Occurring in:. *3-phosphoinositide-dependent protein kinase 1. > Serine/threonine-protein ... Protein kinase domain * Occurring in:. *3-phosphoinositide-dependent protein kinase 1. > ... 3-phosphoinositide-dependent protein kinase 1 Chain: A Molecule details › Chain: A. Length: 310 amino acids. Theoretical weight ...
Brain Sciences | Free Full-Text | Cannabinoids: Well-Suited Candidates for the Treatment of Perinatal Brain Injury | HTML... protein kinase A; PKB/Akt: protein kinase B; ERK: extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; FAK: ... extracellular signal-regulated kinase; JNK: c-Jun N-terminal kinase; FAK: focal adhesion kinase; PI3K: phosphoinositide-3 ... α0 subunits can in turn inhibit voltage dependent Ca2+ channels contributing to the inhibition of membrane depolarization. βγ ... protein kinase A; PKB/Akt: protein kinase B; ERK: ... α0 subunits can in turn inhibit voltage dependent Ca2+ channels ...
The protein kinase ATM is a sensor for reactive oxygen species.. *Abstract ... Online Cover This week features a Research Article that identifies ARAP3 as the downstream effector of phosphoinositide 3- ... Intrinsic differences in mTORC2-dependent Akt activation underlie the region-specific effects of neurofibromatosis-1 on glial ... Membrane fusion proteins cooperate to promote rapid secretory vesicle exocytosis from neuroendocrine cells. ...
This phosphorylation and activation of PKC zeta by PDK-1 is enhanced in the presence of Ptdins-3,4-5-P3. Consistent with the ... Our results have identified PDK-1 as the kinase that phosphorylates and activates PKC zeta in the PI 3-kinase signaling pathway ... Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (PDK-1), which binds with high affinity to ... the protein kinases Akt/PKB and p70S6K. We therefore investigated whether PDK-1 is the kinase that activates PKC zeta. ...
"Presenilin regulates extracellular regulated kinase (Erk) activity by a protein kinase C alpha dependent mechanism," ... mitogen-activated protein kinase; PI3K: phosphoinositide 3-kinase; NF-κB: nuclear factor kappa-light-chain-enhancer of ... D. Wang, Q. Fu, Y. Zhou et al., "Β2 adrenergic receptor, protein kinase a (PKA) and c-Jun N-terminal kinase (JNK) signaling ... calcium/calmodulin-dependent protein kinase 2; and NFAT: nuclear factor of activated T-cells. ...
Pik3r6 - Phosphoinositide 3-kinase regulatory subunit 6 - Mus musculus (Mouse) - Pik3r6 gene & proteinPIK3R5 and its membrane recruitment and beta-gamma G protein dimer-dependent activation requires HRAS bound to PIK3CG. Recruits ... The PIK3CG:PIK3R6 heterodimer is much less sensitive to beta-gamma G proteins than PIK3CG: ... Acts as an adapter to drive activation of PIK3CG by beta-gamma G protein dimers. ... to allow unambiguous identification of a protein.,p>,a href=/help/protein_names target=_top>More...,/a>,/p>Protein namesi. ...
Alpha and beta proteins (a+b) Protein kinase-like (PK-like) Protein kinase-like (PK-like) Protein kinases, catalytic subunit 3- ... phosphoinositide dependent protein kinase- 1 Pdk1 Human (Homo sapiens) [TaxId: 9606] Domain Annotation: CATH CATH Database ( ... Protein Family Annotation Pfam Database Homepage. Chains. Pfam Accession. Pfam Identifier. Pfam Description. Type. Source. ...
... belongs to the family of NLR proteins. Upon activation NALP3 assembles with the adaptor protein ASC to form a protein-complex ... operates in cells in response to phosphoinositide 3-kinase activation and phosphatidylinositol-3,4,5-trisphosphate [PtdIns(3,4, ... Aurora Kinases as Druggable Targets in Cancer Therapy » GLAST Menu Not Found. Skip to content *Home ... 3-Phosphoinositide-dependent protein kinase 1 (PDK1) operates in cells in response to. 3-Phosphoinositide-dependent protein ...
Phosphoinositide-dependent kinase-1 has been shown to interact with: AKT1, PKN2, PRKACA, PRKCD, PRKCI, Protein kinase Mζ, ... "Regulation of protein kinase B/Akt-serine 473 phosphorylation by integrin-linked kinase: critical roles for kinase activity and ... "Identification of regulatory phosphorylation sites in mitogen-activated protein kinase (MAPK)-activated protein kinase-1a/ ... "Protein kinase C isotypes controlled by phosphoinositide 3-kinase through the protein kinase PDK1". Science. 281 (5385): 2042-5 ...
Emerging role of silent information regulator 1 (SIRT1) in hepatocellular carcinoma: a potential therapeutic target |...Ahmad KA, Harris NH, Johnson AD, Lindvall HC, Wang G, Ahmed K. Protein kinase CK2 modulates apoptosis induced by resveratrol ... Imai S, Armstrong CM, Kaeberlein M, Guarente L. Transcriptional silencing and longevity protein Sir2 is an NAD-dependent ... Zschoernig B, Mahlknecht U. Carboxy-terminal phosphorylation of SIRT1 by protein kinase CK2. Biochem Biophys Res Commun. 2009; ... dependent Sir2 histone/protein deacetylases. Proc Natl Acad Sci U S A. 2004;101:8563-8.PubMedPubMedCentralGoogle Scholar ...
Required for G protein-mediated activation of PIK3CG (By similarity). ... Required for recruitment of the catalytic subunit to the plasma membrane via interaction with beta-gamma G protein dimers. ... Translocated to the plasma membrane in a beta-gamma G protein-dependent manner.By similarity. Manual assertion inferred from ... Protein. Similar proteins. Species. Score. Length. Source. Q5SW28. Phosphoinositide-3-kinase, regulatory subunit 5, p101. MOUSE ...
Protein-tyrosine phosphatase Shp-1 is a negative regulator of IL-4- and IL-13-dependent signal transduction. J. Biol. Chem. 273 ... Src family protein-tyrosine kinases alter the function of PTEN to regulate phosphatidylinositol 3-kinase/AKT cascades. J. Biol ... Functionally, the ability of SHP-1 to inhibit CCR7 signaling and protein upregulation resulted in reduced CCL21-dependent BMDC ... Downstream of TLR4, SHP-1 showed increased interaction with several proteins including IL-1R-associated kinase-4, and modulated ...
Gene Expression Literature Detail2003 May;3(2):173-7 Detailed expression data for these assays: 27 results Indicates gene expression was analyzed but not ...
CCAAT/enhancer-binding protein; CaMKKβ, Ca2+/calmodulin-dependent protein kinase kinase β; CBS, cystathionine-β-synthase; CGI- ... p90 ribosomal S6 kinase; PDE3B, phosphodiesterase 3B; PI3K, phosphoinositide 3-kinase; PKA, cAMP-dependent protein kinase; PKB ... AMP-activated protein kinase; aP2, adipocyte-specific fatty acid-binding protein; AS160, Akt substrate of 160 kDa; ATGL, ... and glucocorticoid-induced protein kinase 1; siRNA, small interfering RNA; SREBP-1c, sterol-regulatory-element-binding protein ...
PDK1ActivationPPARPhosphorylationRibosomalCAMP-dependReceptor tyrosinLipidReceptorsMAPKPhosphatidylinositol 3,4,5-trisphosphateGlycogenSubstrateSignal transductionPhosphorylates and activatesPDPK1ExtracellularAntibodyAKT1CGMP-dependMolecularMembraneTranslocationPhosphataseUpstreamHydrophobic motifFamilySuperfamilyAMPKP110InteractionsSequenceTargets
- While PPARα ligand enhanced, PPARα antagonist and siRNA abrogated the effect of NAC on PDK1 promoter activity, protein expression and cell growth. (biomedcentral.com)
- Silencing of p53 and overexpression of p65 blocked the effect of NAC on PDK1 promoter activity and protein expression. (biomedcentral.com)
- Our results show that NAC inhibits PDK1 expression through PPARα-mediated induction of p53 and inhibition of p65 protein expression. (biomedcentral.com)
- NAC induced p53 and reduced p65 protein expression through activation of PPARα. (biomedcentral.com)
- NAC also induced the protein expression of PPARα. (biomedcentral.com)
- The activation of protein kinase B (PKB, also known as c-Akt) is stimulated by insulin or growth factors and results from its phosphorylation at Thr308 and Ser473. (nih.gov)
- Treatment with fMLF induced phosphorylation of soluble N -ethylmaleimide-sensitive factor-attachment protein (SNAP)-23, syntaxins 2, 4, and 6, and Monc18-3. (jimmunol.org)
- However, LY294002 was less effective in inhibiting Munc18-3 phosphorylation. (jimmunol.org)
- These results suggest that PKG and PI3K are involved in degranulation, possibly through phosphorylation of target membrane SNAP receptor proteins and their binding proteins. (jimmunol.org)
- Research conducted thus far has led to the identification of several important regulatory mechanisms for leukocyte degranulation, including elevation of intracellular Ca 2+ concentration, activation of the cytoskeletal contractile apparatus, and phosphorylation of the soluble N -ethylmaleimide-sensitive factor-attachment protein (SNAP) 3 receptor proteins (SNAREs). (jimmunol.org)
- Phosphorylation of Munc18-1 in neuronal cells ( 10 , 11 ) and Munc18-3 and syntaxin 4 in endothelial cells ( 12 ) promotes Munc18-syntaxin dissociation, thereby facilitating vesicular fusion. (jimmunol.org)
- Phosphorylation of syntaxins, Munc18, and SNAP-23 is catalyzed by kinases such as protein kinase C (PKC) ( 12 , 13 , 14 ). (jimmunol.org)
- In mast cells, a mechanism of degranulation induced by FcεRI cross-linking involves recruitment and activation of the tyrosine kinases Lyn and Syk, phosphorylation of several tyrosine residues in FcεRI, activation of phospholipase Cγ (PLCγ), and generation of the second messengers diacylglycerol and inositol trisphosphate ( 1 , 15 ). (jimmunol.org)
- This phosphorylation and activation of PKC zeta by PDK-1 is enhanced in the presence of Ptdins-3,4-5-P3. (nih.gov)
- Using a phospho-Akt substrate antibody, the phosphorylation of actin on an Akt consensus site was detected upon growth factor stimulation, both in cellulo and in vitro , suggesting that actin is a substrate of Akt kinase activity. (mcponline.org)
- Class (I) PI3Ks (PI3Kα, PI3Kβ, PI3Kγ and PI3Kδ) mediate the phosphorylation of the inositol ring at position D3 leading to the generation of PtdIns(3,4,5)P3. (mdpi.com)
- We recently observed that phosphorylation of the AKT hydrophobic motif was dramatically elevated, rather than decreased, in mTOR knockout heart tissues, indicating the existence of other kinase(s) contributing to AKT phosphorylation. (pnas.org)
- Accumulating evidence indicates an mTOR-independent kinase responsible for AKT (S473) phosphorylation. (pnas.org)
- Akt is partially activated through PDK-1-mediated phosphorylation in the catalytic domain, but full activation requires a second phosphorylation event in the hydrophobic motif, which can be mediated by several kinases. (aacrjournals.org)
- Negative feedback regulation of Akt can occur through S6K1, which can catalyze an inhibitory phosphorylation on insulin receptor substrate proteins, abrogating activation of PI3K. (aacrjournals.org)
- Sphingosine 1-phosphate (S1P) is a bioactive lipid mediator, formed by the phosphorylation of sphingosine by sphingosine kinases (SphKs) 1 and 2, which participates in the regulation of a variety of biological activities in different cell types ( Pitson, 2011 ). (frontiersin.org)
- Insulin binding to its receptor results in the tyrosine phosphorylation of insulin receptor substrates (IRS) by the insulin receptor tyrosine kinase (INSR). (genome.jp)
- may catalyze the phosphorylation and activation of protein kinase B [RGD, Feb (origene.com)
- Insulin stimulates glucose transport by activating a cascade of tyrosyl phosphorylation events, initiated by binding of insulin to its receptor ( 2 , 3 ). (diabetesjournals.org)
- BAD phosphorylation induced by interleukin-3 (IL-3) was inhibited by specific inhibitors of phosphoinositide 3-kinase (PI 3-kinase). (sciencemag.org)
- Phosphorylation of BAD results in its cytosolic sequestration by the tau form of 14-3-3 proteins and its inactivation, as the phosphorylated form has reduced ability to bind to membrane Bcl-x L ( 3 ). (sciencemag.org)
- Stimulation of the cells with IL-3 resulted in BAD phosphorylation that was inhibited by concentrations of wortmannin and LY294002 known to specifically inhibit PI 3-kinase activity (Fig. 1 ). (sciencemag.org)
- PI 3-kinase inhibitors block IL-3-induced BAD phosphorylation in FL5.12 cells. (sciencemag.org)
- Membrane-associated Akt is activated by Ser 473 phosphorylation by membrane-associated phosphoinositide-dependent kinase-1 ( 3 ) and Thr 308 phosphorylation by a second incompletely characterized phosphoinositide-dependent kinase-2 ( 4 ). (aacrjournals.org)
- The full activation of Akt1 kinase requires phosphorylation of both Thr-308 and Ser-473 ( 1 ). (physiology.org)
- Here, we merge essential aspects of all three malaria-related communications that were presented at the Evolution of Protein Phosphorylation meeting, and propose an integrated discussion of the specific features of the parasite's kinome and phosphoproteome. (royalsocietypublishing.org)
- Small molecule substrate phosphorylation site inhibitors of protein kinases: approaches and challenges. (ebi.ac.uk)
- Regulation of novel protein kinase C epsilon by phosphorylation. (addgene.org)
- Unexpectedly, AKT kinase activity recovered 8 hours after AZD8055 treatment, as evidenced by an increase in phospho AKT (Thr308) and concomitant phosphorylation of its substrates ( 1 ). (aacrjournals.org)
- AKT phosphorylation on Thr308 is essentially required for kinase activity ( 8 ). (aacrjournals.org)
- Phosphorylation on Thr308 increases AKT kinase activity by at least 100-fold, whereas phosphorylation on Ser473 mediates stabilization of the active conformation of the kinase, increasing activity by roughly another 10-fold ( 9 ). (aacrjournals.org)
- PKA-cat phosphorylation of Beta-2 adrenergic receptor leads to its activation switch from G-protein alpha-i family to G-protein alpha-s . (bio-rad.com)
- Phosphorylation of extracellular signal-regulated kinase 1/2 was partially blocked by ZD1839 and celecoxib alone and was completely blocked by the combination of both agents. (aacrjournals.org)
- In work reported in this issue of the Biochemical Journal , García-Martínez and Alessi have revealed the identity of a 'PDK2' kinase that catalyses Ser 422 phosphorylation as mTORC2 (mammalian target of rapamycin complex 2), a multiprotein kinase that phosphorylates a similar site in PKB (protein kinase B). (portlandpress.com)
- Post-translational modifications, particularly reversible protein phosphorylation, endow selectivity by transmitting the signalling information into altered function of only particular downstream components. (portlandpress.com)
- Phosphorylation of CPI-17, an inhibitor of myosin phosphatase, by protein kinase N. (wikipathways.org)
- Domain-specific phosphorylation of vimentin and glial fibrillary acidic protein by PKN. (wikipathways.org)
- The expression of vascular cell adhesion molecule (VCAM)-1, intercellular adhesion molecule (ICAM)-1, ICAM-2, and E-selectin, as well as the phosphorylation of the NF-κB inhibitory protein IκB-α and Akt, were examined by immunoblot analysis. (arvojournals.org)
- B and C) Naive P14-LCMV CD8+ T cells ± TCR (gp33-41/anti-CD28) stimulation were assayed for glucose uptake (B) and lactate production (C). (D) Immunoblot analysis of naive OTI CD8+ T cells ± TCR (SIINFEKL) stimulation for 20 h. mTORC1 activity was determined by analyzing the phosphorylation of target sequences on S6K1 (T389 and S241/242) and phosphorylation of the S6K1 substrate S6 ribosomal protein. (nih.gov)
- Characterization of regulatory events associated with membrane targeting of p90 ribosomal S6 kinase 1. (addgene.org)
- Ribosomal protein S6 kinase alpha-2 is an enzyme that in humans is encoded by the RPS6KA2 gene . (wikidoc.org)
- This gene encodes a member of the RSK (ribosomal S6 kinase) family of serine and threonine kinases . (wikidoc.org)
- Mechanistically, it is known that GLP-1 increases cyclic AMP in pancreatic β-cells by its action on the Gs-coupled GLP-1 receptor, which in turn, activates cAMP-dependent protein kinase A (PKA) ( 21 ). (diabetesjournals.org)
- The serine/threonine kinase Akt/PKB 1 belongs to the cAMP-dependent protein kinase A/protein kinase G/protein kinase C (AGC) superfamily of protein kinases that share structural homology within their catalytic domain and have similar mechanisms of activation ( 1 ). (mcponline.org)
- PI3K signaling is initiated by receptor tyrosine kinases (RTK) or G-protein-coupled receptors located at the cell surface, and some oncogenic proteins, such as RAS. (aacrjournals.org)
- The product of this gene belongs to a small family of adapter proteins that are known to interact with a number of receptor tyrosine kinases and signaling molecules. (wikipedia.org)
- The lymphocyte-specific kinase Lck is a member of the Src family of non-receptor tyrosine kinases. (ebi.ac.uk)
- A global analysis of cellular phospholipids demonstrates that in gliding ookinetes PKG controls phosphoinositide biosynthesis, possibly through the subcellular localisation or activity of lipid kinases. (nih.gov)
- Recent reports have also shown that the phosphoinositide-dependent protein kinase-1 (PDK-1), which binds with high affinity to the PI 3-kinase lipid product phosphatidylinositol-3,4,5-trisphosphate (Ptdins-3,4,5-P3), phosphorylates and potently activates two other PI 3-kinase targets, the protein kinases Akt/PKB and p70S6K. (nih.gov)
- Glucose and lipid metabolism are largely dependent on mitochondria to generate energy in cells. (ahajournals.org)
- Finally, expression of the gene for the lipid phosphatase PTEN, which dephosphorylates PtdIns(3,4,5)P3, inhibits EGF signaling and translocation of Gab1 to the plasma membrane. (asm.org)
- This protein contains a lipid kinase catalytic domain as well as a C-terminal C2 domain, a characteristic of class II PI3-kinases. (origene.com)
- Since G protein coupled receptors (GPCRs) are target of forty percent of clinically used drugs, here we discuss the newly identified cardioprotective agents that bind GPCRs of adrenalin, adenosine, melatonin, ghrelin, galanin, apelin, prokineticin and cannabidiol. (frontiersin.org)
- S1P is synthesized by sphingosine kinases (SphKs) and many of its actions are mediated by S1P specific cell surface receptors (S1P 1-5 ), although different intracellular targets of S1P have been identified. (frontiersin.org)
- This gene encodes a growth factor receptor-binding protein that interacts with insulin receptors and insulin-like growth-factor receptors. (wikipedia.org)
- Activation of sphingosine kinase by a variety of agonists increases intracellular S1P, which in turn can function intracellularly as a second messenger or be secreted out of the cell and act extracellularly by binding to and signaling through S1P receptors in autocrine and/or paracrine manners. (aspetjournals.org)
- Gene deletion studies and reverse pharmacology have provided evidence that many of the biological effects of S1P are mediated via five specific G protein-coupled receptors (GPCRs), now designated S1P 1-5 ( Fig. 3 ). (aspetjournals.org)
- These receptors are heteromeric protein complexes with multiple subunits, each possessing transmembrane regions, and all arranged to form a ligand-gated ion channel. (antibodies-online.com)
- This gene product belongs to a family of glutamate receptors that are sensitive to alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionate (AMPA), and function as ligand-activated cation channels. (antibodies-online.com)
- PI 3-kinase is recruited and activated during the intracellular signal transduction of many receptors and has been implicated in the signaling of survival factors ( 5 ). (sciencemag.org)
- However, a number of receptors also rely on a growing family of accessory, or docking, proteins that are recruited to the plasma membrane, become tyrosine phosphorylated, and act as centers for assembly of multiprotein complexes. (asm.org)
- The National Cancer Institute, Division of Cancer Prevention has recently ublished a series of reviews on mechanism-based targets for cancer-preventive intervention including peroxisome proliferator-activated receptors ( 1 ), inducible nitric oxide synthase ( 2 ), and epigenetic modulators, primarily histone deacetylases and DNA methyl transferases ( 3 , 4 ). (aacrjournals.org)
- Signaling via G-protein-coupled receptors undergoes desensitization after prolonged agonist exposure. (biomedsearch.com)
- HER-2 is a member of the erbB family of receptors, which includes epidermal growth factor receptor (EGFR)/erbB1/HER-1, erbB-2/neu/HER-2, erbB3/HER-3, and erbB4/HER-4. (aacrjournals.org)
- Although HER-2 has no known ligand, it is the preferred heterodimer of the other receptors ( 3 ). (aacrjournals.org)
- GRB2 is part of the cascade including SOS, RAS, RAF and MEK that leads to activation of mitogen-activated protein kinase (MAPK) and mitogenic responses in the form of gene transcription. (genome.jp)
- Upon stimulation, a sequential three-part protein kinase cascade is initiated, consisting of a MAP kinase kinase kinase (MAPKKK or MAP3K), a MAP kinase kinase (MAPKK or MAP2K), and a MAP kinase (MAPK). (cellsignal.com)
- Chronic DAMGO desensitization was heterologous in nature and significantly attenuated by blocking the activity of PI3K or mitogen-activated protein kinase (MAPK). (biomedsearch.com)
- Our data suggest that the PI3Kcascade involving MAPK and Akt enhances micro-opioid desensitization via postreceptor modifications that interfere with G-protein-effector interactions. (biomedsearch.com)
- PDPK1 functions downstream of PI3K through PDPK1's interaction with membrane phospholipids including phosphatidylinositols, phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. (wikipedia.org)
- PI3K indirectly regulates PDPK1 by phosphorylating phosphatidylinositols which in turn generates phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate. (wikipedia.org)
- The PH domain functions mainly in the interaction of PDPK1 with phosphatidylinositol (3,4)-bisphosphate and phosphatidylinositol (3,4,5)-trisphosphate which is important in localization and activation of some of membrane associated PDPK1's substrates including AKT. (wikipedia.org)
- PI3Ks are an enzyme family that phosphorylate PtdIns (Phosphatidylinositol) to generate phosphatidylinositol 3,4,5-trisphosphate (PIP3). (antibodies-online.com)
- The product of the phosphatidylinositol 3-kinase reaction, phosphatidylinositol 3,4,5-trisphosphate, may serve as a link to the activation of 3-phosphoinositide-dependent protein kinase-1 ( 9 ), which in turn phosphorylates Akt1 kinase, also referred to as protein kinase B or RAC kinase, at Thr-308 ( 2 ). (physiology.org)
- Activation of PRK1 by phosphatidylinositol 4,5-bisphosphate and phosphatidylinositol 3,4,5-trisphosphate. (wikipathways.org)
- Protein kinase B kinases that mediate phosphatidylinositol 3, 4, 5-trisphosphate-dependent activation of protein kinase B. Science. (springermedizin.de)
- Akt in turn deactivates glycogen synthase kinase 3 (GSK-3), leading to activation of glycogen synthase (GYS) and thus glycogen synthesis. (genome.jp)
- Differential effects of constitutively active phosphatidylinositol 3-kinase on glucose transport, glycogen synthase activity, and DNA synthesis in 3T3-L1 adipocytes. (harvard.edu)
- Fatty acid infusion selectively impairs insulin action on Akt1 and protein kinase C lambda /zeta but not on glycogen synthase kinase-3. (harvard.edu)
- The effect of Ptdlns(3,4,5)P3/Ptdlns(3,4)P2 in the activation of PKB alpha is at least partly substrate directed. (nih.gov)
- Following IGF-1 and insulin stimulation, the tyrosine-phosphorylated pYMXM and pYXXM motifs in the insulin receptor substrate (IRS) proteins bind to class Ia PI 3-kinase, thereby increasing its activity ( 2 , 43 ). (asm.org)
- The first complex, mTORC1, is a direct target of rapamycin (in association with the cellular protein, FKBP12), and contains the substrate-binding scaffold protein raptor, a small WD40-repeat protein, mLst8/GβL and PRAS40. (portlandpress.com)
- Site recognition and substrate screens for PKN family proteins. (wikipathways.org)
- Other signal transduction proteins interact with IRS including GRB2. (genome.jp)
- Phosphoinositides (PIs) play major roles in cell signal transduction. (dissertations.se)
- Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Balpha. (nih.gov)
- In vitro, PDK-1 phosphorylates and activates PKC zeta in a Ptdins-3,4,5-P3-enhanced manner. (nih.gov)
- Characterization of a 3-phosphoinositide-dependent protein kinase which phosphorylates and activates protein kinase Bα. (springermedizin.de)
- In the field of biochemistry, PDPK1 refers to the protein 3-phosphoinositide-dependent protein kinase-1, an enzyme which is encoded by the PDPK1 gene in humans. (wikipedia.org)
- PDPK1 is a master kinase, which is crucial for the activation of AKT/PKB and many other AGC kinases including PKC, S6K, SGK. (wikipedia.org)
- PDPK1 stands for 3-phosphoinositide-dependent protein kinase 1. (wikipedia.org)
- Several PDPK1 substrates including S6K and Protein kinase C, require the binding at this docking site. (wikipedia.org)
- The activation of PDPK1's main effector, AKT, is believed to require a proper orientation of the kinase and PH domains of PDPK1 and AKT at the membrane. (wikipedia.org)
- This affinity purified antibody was prepared from whole rabbit serum produced by repeated immunizations with a synthetic peptide corresponding to a region near the C-terminal of human PDPK1 protein. (novusbio.com)
- Homo sapiens 3-phosphoinositide dependent protein kinase-1 (PDPK1), mRNA. (abnova.com)
- Liver fibrosis is an excess production of extracellular matrix proteins as a result of chronic liver disease which leads to cell death and organ dysfunction. (frontiersin.org)
- Cysteine-rich angiogenic inducer 61 (Cyr61) is an extracellular matrix protein involved in the transduction of growth factor and hormone signaling. (pubmedcentralcanada.ca)
- Cystein-rich angiogenic inducer 61 (Cyr61), also called CCN1, is an extracellular matrix protein involved in growth factor transduction, hormone signaling, and mechanical stress response mediation [ 3 ]. (pubmedcentralcanada.ca)
- They include the epidermal growth factor receptor (EGFR, ErbB-1, HER1), that when activated by ligand binding to its extracellular domain, homodimerizes or heterodimerizes with any of three other family members, ErbB-2 (HER2), ErbB-3 (HER3), and ErbB-4 (HER4), leading to autophosphorylation of cytoplasmic COOH-terminal tyrosine residues. (aacrjournals.org)
- Incubate membrane with Anti-rabbit IgG, HRP-linked Antibody ( #7074 at 1:2000) and anti-biotin, HRP-linked Antibody ( #7075 at 1:1000-1:3000) to detect biotinylated protein markers in 10 ml of blocking buffer with gentle agitation for 1 hr at room temperature. (cellsignal.com)
- PI3K C2 alpha antibody [C C-term detects PIK3C2A protein at cytosol on human hepatoma by immunohistochemical analysis. (genetex.com)
- Interestingly it has been suggested that activation of Akt1 by Her2/phosphatidylinositol 3-kinase (PI3K) plays an important role in mediating multidrug resistance in human breast cancer cells, and Akt may therefore be a novel molecular target for therapies against breast cancer (2, 4). (mcponline.org)
- The serine-threonine protein kinase encoded by the AKT1 gene is catalytically inactive in serum-starved primary and immortalized fibroblasts. (antibodies-online.com)
- Basal and insulin-stimulated activity of Akt1 kinase and uptake of 2-deoxy- d -glucose (2-DG) were measured in soleus (slow-twitch) and plantaris (fast-twitch) muscles of rats at 1 and 3 days after sectioning the sciatic nerve in one hindlimb of the animals. (physiology.org)
- At 1 day after surgery, the insulin-stimulated activity of Akt1 kinase in denervated soleus and plantaris muscles remained unchanged, but the insulin-stimulated 2-DG uptake by these muscles was reduced by 71 and 61%, respectively, compared with the corresponding muscles of the contralateral sham (control) hindlimb. (physiology.org)
- At 3 days, the insulin-stimulated activity of Akt1 kinase in the denervated soleus and plantaris muscles was 86 and 71% lower, respectively, than in their sham counterparts. (physiology.org)
- None of the denervated muscles showed a decrease in the abundance of Akt1 kinase. (physiology.org)
- Initially, they involve only mechanisms downstream of Akt1 kinase ( day 1 ), whereas at day 3 they also involve mechanisms upstream of, and including, Akt1 kinase. (physiology.org)
- The role of Akt1 kinase in mediating the insulin-induced stimulation of glucose uptake is suggested by the observation that transfection of a constitutively active Akt1 kinase into 3T3-L1 adipocytes has an insulin-like effect on the translocation of GLUT-4 transporter to the plasma membrane and glucose uptake ( 13 ). (physiology.org)
- We examined the roles of cGMP-dependent protein kinase (PKG) and PI3K in degranulation induced by fMLF and by FcεRI cross-linking. (jimmunol.org)
- Using the motility of Plasmodium berghei ookinetes as a signalling paradigm, we show that the cyclic guanosine monophosphate (cGMP)-dependent protein kinase, PKG, maintains the elevated level of cytosolic Ca²⁺ required for gliding motility. (nih.gov)
- Overall, brain health and successful aging are characterized by limited protein aggregation, with a distinct molecular signature of maintained autophagy function. (intechopen.com)
- a ) Chemical structure of Tan-IIA, C 19 H 18 O 3 , molecular weight: 294.34. (nature.com)
- Binding of calcium to the protein calmodulin leads to molecular reorganization that enables interaction with target peptides and activation of downstream processes. (dissertations.se)
- The scope of celecoxib-modulated molecular alterations can best be studied by applying global approaches at the transcription and/or protein levels. (aacrjournals.org)
- Loading of prestained molecular weight markers ( #13953 , 5 µl/lane) to verify electrotransfer and biotinylated protein ladder ( #7727 , 10 µl/lane) to determine molecular weights are recommended. (cellsignal.com)
- SNAREs, which were initially identified in neuronal cells for their function in membrane fusion ( 5 ), include vesicular SNAREs such as vesicle-associated membrane proteins, target membrane SNAREs (t-SNAREs) such as syntaxins, and the Sec1/Munc18 family of proteins that serve as binding partners of t-SNAREs. (jimmunol.org)
- The PIK3CG:PIK3R6 heterodimer is much less sensitive to beta-gamma G proteins than PIK3CG:PIK3R5 and its membrane recruitment and beta-gamma G protein dimer-dependent activation requires HRAS bound to PIK3CG. (uniprot.org)
- Membrane fusion proteins cooperate to promote rapid secretory vesicle exocytosis from neuroendocrine cells. (sciencemag.org)
- Once generated, 3′-phosphoinositides bind to the pleckstrin homology domains of 3′-phosphoinositide-dependent kinase-1 (PDK-1) and Akt and cause translocation of each kinase to the plasma membrane, where both are activated. (aacrjournals.org)
- Eight mammalian PI3-Ks are divided into three main classes: class I PI3-Ks phosphorylate membrane phosphatidylinositol to give PI(3, 4, 5)P 3 that recruits the cytoplasmic serine/threonine kinase Akt by binding to its pleckstrin homology domain. (aacrjournals.org)
- This chromosomal translocation induces the formation of the chimeric protein nucleophosmin-anaplastic lymphoma kinase (NPM-ALK), which possesses significant oncogenic potential resulting from the constitutive activation of the tyrosine kinase ALK. (bloodjournal.org)
- 9 , 10 This chromosomal translocation leads to the generation of the chimeric protein NPM-ALK. (bloodjournal.org)
- Identifying these tumors with this translocation became clinically feasible after the production of antibodies that specifically interact with chimeric NPM-ALK and full-length ALK proteins. (bloodjournal.org)
- Tan-IIA also induced ER stress in prostate cancer cells: activation and nuclear translocation of GADD153/CCAAT/enhancer-binding protein-homologous protein (CHOP) were identified, and increased expression of the downstream molecules GRP78/BiP, inositol-requiring protein-1α and GADD153/CHOP were evidenced. (nature.com)
- 1995). "RSK3 encodes a novel pp90rsk isoform with a unique N-terminal sequence: growth factor-stimulated kinase function and nuclear translocation" . (wikidoc.org)
- There is high degree of consensus that in AD kinase and/or phosphatase activities are deregulated, resulting in hyperphosphorylation of TAU. (hindawi.com)
- PtdIns(3,4,5)P3 can be dephosphorylated by several phosphatases, of which the best known is the 3-phosphatase PTEN (phosphatase and tensin homolog). (mdpi.com)
- The tumor suppressor phosphatase and tensin homologue deleted on chromosome 10 (PTEN) opposes the action of PI3K by dephosphorylating 3′-phosphoinositides. (aacrjournals.org)
- The tumor suppressor protein PTEN (phosphatase and tensin homologue deleted on chromosome 10), a dual specificity tyrosine-threonine/PI-3 phosphatase, prevents the accumulation of PI(3,4,5)P 3 and attenuates PI3-K signaling ( 9 ). (aacrjournals.org)
- These results reveal a novel positive feedback loop, modulated by PTEN, in which PI-3 kinase functions as both an upstream regulator and a downstream effector of Gab1 in signaling via the EGFR. (asm.org)
- Here we show that the atypical IκB kinase ε and TANK-binding kinase 1 (IKKε/TBK1) phosphorylate AKT on both the hydrophobic motif and the activation loop in a manner dependent on PI3K signaling. (pnas.org)
- Collectively, these data provide compelling evidence for the existence of other AKT hydrophobic motif kinases besides mTORC2. (pnas.org)
- NALP3 (formerly known as cryopyrin) belongs to the family of NLR proteins. (exposed-skin-care.net)
- AGC Ser/Thr protein kinase family. (abcam.com)
- Proteins of the Bcl-2 family are important regulators of cell death in mammalian cells ( 1 ). (sciencemag.org)
- Background: Mitogen-activated protein kinases (MAPKs) are a widely conserved family of serine/threonine protein kinases involved in many cellular programs, such as cell proliferation, differentiation, motility, and death. (cellsignal.com)
- the amino acid composition of this pocket is unique to Src family kinases. (ebi.ac.uk)
- PKA-cat activates RAP1A member of RAS oncogene family ( RAP-1A )/ v-raf murine sarcoma viral oncogene homolog B1 ( B-Raf )/ Mitogen-activated protein kinase kinase 2 and 1 ( MEK2(MAP2K2) and MEK1(MAP2K1) )/ Erk [ 6 ]. (bio-rad.com)
- G-protein alpha-i family activation releases complex of G-protein beta/gamma , which activates c-src tyrosine kinase ( c-Src ) [ 12 ]. (bio-rad.com)
- The activation of the AGC (protein kinase A/protein kinase G/protein kinase C)-family kinase SGK1 (serum- and glucocorticoid-induced kinase 1) by insulin via PI3K (phosphoinositide 3-kinase) signalling has been appreciated for almost 10 years. (portlandpress.com)
- Domin J, Waterfield M. Using structure to define the function of phosphoinositide 3-kinase family members. (springermedizin.de)
- Belongs to the protein kinase superfamily. (abcam.com)
- This transmembrane receptor tyrosine kinase belongs to the insulin receptor superfamily. (bloodjournal.org)
- AMPK (AMP-activated protein kinase) is a key regulator of cellular and whole-body energy balance. (clinsci.org)
- Src kinase ( 20 ), phospholipase D (PLD) ( 17 , 13 ), proline-rich tyrosine kinase 2 ( 13 ), and AMP-activated kinase (AMPK) ( 13 ). (physiology.org)
- Earlier, we have generated GFP-fusion proteins of p110α and p110β and expressed them in normal and cancer cell-lines to investigate their subcellular localization and their role in various activities. (springermedizin.de)
- To know whether p110α and p110β are involved in protecting MCF-7 breast cancer cells against oxidative stress, we subjected MCF-7 cells to H2O2 treatment and observed a dose dependent decrease in cell viability and a marked increase in the levels of pro-apoptotic markers which include PARP, Bcl-2, Bax and procaspase-9. (springermedizin.de)
- Phosphoinositide 3-kinase cascade facilitates mu-opioid desensitization in sensory neurons by altering G-protein-effector interactions. (biomedsearch.com)
- Using the prepulse facilitation (PPF) test, we further examined changes in the voltage-dependent component of DAMGO action that requires direct interactions between betagamma subunits of G-proteins and Ca2+ channels. (biomedsearch.com)
- DAMGO-induced PPF was diminished after chronic treatment, suggesting disruption of G-protein-channel interactions. (biomedsearch.com)
- Note that the 'protein existence' evidence does not give information on the accuracy or correctness of the sequence(s) displayed. (uniprot.org)
- Carrier-protein conjugated synthetic peptide encompassing a sequence within the C-terminus region of human PI3K C2 alpha. (genetex.com)
- Kinase packing defects as drug targets. (ebi.ac.uk)
- PI 3-kinase phosphorylates inositol lipids that act as second messengers for several targets, including the serine-threonine Akt kinase ( 6 , 7 , 8 ). (sciencemag.org)
- 800 human members ( 11 ) among which receptor protein tyrosine kinases are frequently targets for cancer therapy. (aacrjournals.org)