beta-Adrenergic Receptor Kinases: G-protein-coupled receptor kinases that mediate agonist-dependent PHOSPHORYLATION and desensitization of BETA-ADRENERGIC RECEPTORS.G-Protein-Coupled Receptor Kinase 2: A ubiquitously expressed G-protein-coupled receptor kinase subtype that has specificity for the agonist-occupied form of BETA-ADRENERGIC RECEPTORS. It may play an essential role in regulating myocardial contractile response.G-Protein-Coupled Receptor Kinase 5: A G-protein-coupled receptor kinase subtype that is primarily expressed in the MYOCARDIUM and may play a role in the regulation of cardiac functions.G-Protein-Coupled Receptor Kinases: A family of serine-threonine kinases that are specific for G-PROTEIN-COUPLED RECEPTORS. They are regulatory proteins that play a role in G-protein-coupled receptor densensitization.G-Protein-Coupled Receptor Kinase 3: A ubiquitously expressed G-protein-coupled receptor kinase subtype that has specificity for the agonist-occupied form of BETA-ADRENERGIC RECEPTORS and a variety of other G-PROTEIN-COUPLED RECEPTORS. Although it is highly homologous to G-PROTEIN-COUPLED RECEPTOR KINASE 2, it is not considered to play an essential role in regulating myocardial contractile response.Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.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.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.G-Protein-Coupled Receptor Kinase 1: A PROTEIN-SERINE-THREONINE KINASE that is found in PHOTORECEPTOR CELLS. It mediates light-dependent PHOSPHORYLATION of RHODOPSIN and plays an important role in PHOTOTRANSDUCTION.G-Protein-Coupled Receptor Kinase 4: A G-protein-coupled receptor kinase subtype that is primarily expressed in the TESTES and BRAIN. Variants of this subtype exist due to multiple alternative splicing of its mRNA.GTP-Binding Proteins: Regulatory proteins that act as molecular switches. They control a wide range of biological processes including: receptor signaling, intracellular signal transduction pathways, and protein synthesis. Their activity is regulated by factors that control their ability to bind to and hydrolyze GTP to GDP. EC 3.6.1.-.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.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.Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.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 Kinase Inhibitors: Agents that inhibit PROTEIN KINASES.Arrestins: Regulatory proteins that down-regulate phosphorylated G-protein membrane receptors, including rod and cone photoreceptors and adrenergic receptors.Heterotrimeric GTP-Binding Proteins: GTP-BINDING PROTEINS that contain three non-identical subunits. They are found associated with members of the seven transmembrane domain superfamily of G-PROTEIN-COUPLED RECEPTORS. Upon activation the GTP-BINDING PROTEIN ALPHA SUBUNIT of the complex dissociates leaving a dimer of a GTP-BINDING PROTEIN BETA SUBUNIT bound to a GTP-BINDING PROTEIN GAMMA SUBUNIT.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)Receptor Protein-Tyrosine Kinases: A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity.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.Protein-Tyrosine Kinases: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.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.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.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.Cell Line: Established cell cultures that have the potential to propagate indefinitely.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.GTP-Binding Protein beta Subunits: Heterotrimeric GTP-binding protein subunits that tightly associate with GTP-BINDING PROTEIN GAMMA SUBUNITS. A dimer of beta and gamma subunits is formed when the GTP-BINDING PROTEIN ALPHA SUBUNIT dissociates from the GTP-binding protein heterotrimeric complex. The beta-gamma dimer can play an important role in signal transduction by interacting with a variety of second messengers.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.Receptor, Insulin: A cell surface receptor for INSULIN. It comprises a tetramer of two alpha and two beta subunits which are derived from cleavage of a single precursor protein. The receptor contains an intrinsic TYROSINE KINASE domain that is located within the beta subunit. Activation of the receptor by INSULIN results in numerous metabolic changes including increased uptake of GLUCOSE into the liver, muscle, and ADIPOSE TISSUE.RGS Proteins: A large family of evolutionarily conserved proteins that function as negative regulators of HETEROTRIMERIC GTP-BINDING PROTEINS. RGS PROTEINS act by increasing the GTPase activity of the G alpha subunit of a heterotrimeric GTP-binding protein, causing it to revert to its inactive (GDP-bound) form.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.GTP-Binding Protein gamma Subunits: Heterotrimeric GTP-binding protein subunits that tightly associate with GTP-BINDING PROTEIN BETA SUBUNITS. A dimer of beta and gamma subunits is formed when the GTP-BINDING PROTEIN ALPHA SUBUNIT dissociates from the GTP-binding protein heterotrimeric complex. The beta-gamma dimer can play an important role in signal transduction by interacting with a variety of second messengers.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.Kinetics: The rate dynamics in chemical or physical systems.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.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.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.GTP-Binding Protein alpha Subunits, Gi-Go: A family of heterotrimeric GTP-binding protein alpha subunits that were originally identified by their ability to inhibit ADENYLYL CYCLASES. Members of this family can couple to beta and gamma G-protein subunits that activate POTASSIUM CHANNELS. The Gi-Go part of the name is also spelled Gi/Go.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.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.GTP-Binding Protein alpha Subunits: The GTPase-containing subunits of heterotrimeric GTP-binding proteins. When dissociated from the heterotrimeric complex these subunits interact with a variety of second messenger systems. Hydrolysis of GTP by the inherent GTPase activity of the subunit causes it to revert to its inactive (heterotrimeric) form. The GTP-Binding protein alpha subunits are grouped into families according to the type of action they have on second messenger systems.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.GTP-Binding Protein alpha Subunits, Gq-G11: A family of heterotrimeric GTP-binding protein alpha subunits that activate TYPE C PHOSPHOLIPASES dependent signaling pathways. The Gq-G11 part of the name is also spelled Gq/G11.Guanosine 5'-O-(3-Thiotriphosphate): Guanosine 5'-(trihydrogen diphosphate), monoanhydride with phosphorothioic acid. A stable GTP analog which enjoys a variety of physiological actions such as stimulation of guanine nucleotide-binding proteins, phosphoinositide hydrolysis, cyclic AMP accumulation, and activation of specific proto-oncogenes.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Cell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.GTP-Binding Protein Regulators: Proteins that regulate the signaling activity of GTP-BINDING PROTEINS. They are divided into three categories depending upon whether they stimulate GTPase activity (GTPASE-ACTIVATING PROTEINS), inhibit release of GDP; (GUANINE NUCLEOTIDE DISSOCIATION INHIBITORS); or exchange GTP for GDP; (GUANINE NUCLEOTIDE EXCHANGE FACTORS).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).Pertussis Toxin: One of the virulence factors produced by BORDETELLA PERTUSSIS. It is a multimeric protein composed of five subunits S1 - S5. S1 contains mono ADPribose transferase activity.Receptors, G-Protein-Coupled: The largest family of cell surface receptors involved in SIGNAL TRANSDUCTION. They share a common structure and signal through HETEROTRIMERIC G-PROTEINS.Receptors, Adrenergic, beta-2: A subclass of beta-adrenergic receptors (RECEPTORS, ADRENERGIC, BETA). The adrenergic beta-2 receptors are more sensitive to EPINEPHRINE than to NOREPINEPHRINE and have a high affinity for the agonist TERBUTALINE. They are widespread, with clinically important roles in SKELETAL MUSCLE; LIVER; and vascular, bronchial, gastrointestinal, and genitourinary SMOOTH MUSCLE.Tyrosine: A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin.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).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.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.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.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.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.Isoenzymes: Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.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.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.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.Virulence Factors, Bordetella: A set of BACTERIAL ADHESINS and TOXINS, BIOLOGICAL produced by BORDETELLA organisms that determine the pathogenesis of BORDETELLA INFECTIONS, such as WHOOPING COUGH. They include filamentous hemagglutinin; FIMBRIAE PROTEINS; pertactin; PERTUSSIS TOXIN; ADENYLATE CYCLASE TOXIN; dermonecrotic toxin; tracheal cytotoxin; Bordetella LIPOPOLYSACCHARIDES; and tracheal colonization factor.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.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.PhosphoproteinseIF-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.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.Rhodopsin: A purplish-red, light-sensitive pigment found in RETINAL ROD CELLS of most vertebrates. It is a complex consisting of a molecule of ROD OPSIN and a molecule of 11-cis retinal (RETINALDEHYDE). Rhodopsin exhibits peak absorption wavelength at about 500 nm.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.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.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.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.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 18.104.22.168.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.Cricetinae: A subfamily in the family MURIDAE, comprising the hamsters. Four of the more common genera are Cricetus, CRICETULUS; MESOCRICETUS; and PHODOPUS.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.Receptor, Epidermal Growth Factor: A cell surface receptor involved in regulation of cell growth and differentiation. It is specific for EPIDERMAL GROWTH FACTOR and EGF-related peptides including TRANSFORMING GROWTH FACTOR ALPHA; AMPHIREGULIN; and HEPARIN-BINDING EGF-LIKE GROWTH FACTOR. The binding of ligand to the receptor causes activation of its intrinsic tyrosine kinase activity and rapid internalization of the receptor-ligand complex into the cell.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.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.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.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.Thymidine Kinase: An enzyme that catalyzes the conversion of ATP and thymidine to ADP and thymidine 5'-phosphate. Deoxyuridine can also act as an acceptor and dGTP as a donor. (From Enzyme Nomenclature, 1992) EC 22.214.171.124.Brassinosteroids: Plant steroids ubiquitously distributed throughout the plant kingdom. They play essential roles in modulating growth and differentiation of cells at nanomolar to micromolar concentrations.Receptors, Adrenergic, beta: One of two major pharmacologically defined classes of adrenergic receptors. The beta adrenergic receptors play an important role in regulating CARDIAC MUSCLE contraction, SMOOTH MUSCLE relaxation, and GLYCOGENOLYSIS.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.GTP-Binding Protein alpha Subunits, Gs: A family of heterotrimeric GTP-binding protein alpha subunits that activate ADENYLYL CYCLASES.Adenylate Cyclase: An enzyme of the lyase class that catalyzes the formation of CYCLIC AMP and pyrophosphate from ATP. EC 126.96.36.199.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.Phosphotransferases (Alcohol Group Acceptor): A group of enzymes that transfers a phosphate group onto an alcohol group acceptor. EC 2.7.1.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.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.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.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 188.8.131.52), it is commonly used in the literature to refer to broad variety of enzymes that specifically catalyze the hydrolysis of PHOSPHATIDYLINOSITOLS.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.CHO Cells: CELL LINE derived from the ovary of the Chinese hamster, Cricetulus griseus (CRICETULUS). The species is a favorite for cytogenetic studies because of its small chromosome number. The cell line has provided model systems for the study of genetic alterations in cultured mammalian cells.Receptors, Cell Surface: Cell surface proteins that bind signalling molecules external to the cell with high affinity and convert this extracellular event into one or more intracellular signals that alter the behavior of the target cell (From Alberts, Molecular Biology of the Cell, 2nd ed, pp693-5). Cell surface receptors, unlike enzymes, do not chemically alter their ligands.Steroids, Heterocyclic: Steroidal compounds in which one or more carbon atoms in the steroid ring system have been substituted with non-carbon atoms.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.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.CDC2-CDC28 Kinases: A family of cell cycle-dependent kinases that are related in structure to CDC28 PROTEIN KINASE; S CEREVISIAE; and the CDC2 PROTEIN KINASE found in mammalian species.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.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.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.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.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.Arrestin: A 48-Kd protein of the outer segment of the retinal rods and a component of the phototransduction cascade. Arrestin quenches G-protein activation by binding to phosphorylated photolyzed rhodopsin. Arrestin causes experimental autoimmune uveitis when injected into laboratory animals.Receptors, Muscarinic: One of the two major classes of cholinergic receptors. Muscarinic receptors were originally defined by their preference for MUSCARINE over NICOTINE. There are several subtypes (usually M1, M2, M3....) that are characterized by their cellular actions, pharmacology, and molecular biology.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.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.Aurora Kinases: A family of highly conserved serine-threonine kinases that are involved in the regulation of MITOSIS. They are involved in many aspects of cell division, including centrosome duplication, SPINDLE APPARATUS formation, chromosome alignment, attachment to the spindle, checkpoint activation, and CYTOKINESIS.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.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.Phosphotyrosine: An amino acid that occurs in endogenous proteins. Tyrosine phosphorylation and dephosphorylation plays a role in cellular signal transduction and possibly in cell growth control and carcinogenesis.Phospholipase C beta: A phosphoinositide phospholipase C subtype that is primarily regulated by its association with HETEROTRIMERIC G-PROTEINS. It is structurally related to PHOSPHOLIPASE C DELTA with the addition of C-terminal extension of 400 residues.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.Tetradecanoylphorbol Acetate: A phorbol ester found in CROTON OIL with very effective tumor promoting activity. It stimulates the synthesis of both DNA and RNA.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).Spodoptera: A genus of owlet moths of the family Noctuidae. These insects are used in molecular biology studies during all stages of their life cycle.Guanosine Triphosphate: Guanosine 5'-(tetrahydrogen triphosphate). A guanine nucleotide containing three phosphate groups esterified to the sugar moiety.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Cell Line, Tumor: A cell line derived from cultured tumor cells.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.Diacylglycerol Kinase: An enzyme of the transferase class that uses ATP to catalyze the phosphorylation of diacylglycerol to a phosphatidate. EC 184.108.40.206.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.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.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.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.GTP-Binding Protein alpha Subunit, Gi2: A PERTUSSIS TOXIN-sensitive GTP-binding protein alpha subunit. It couples with a variety of CELL SURFACE RECEPTORS, has been implicated in INTERLEUKIN-12 production, and may play a role in INFLAMMATORY BOWEL DISEASES.COS Cells: CELL LINES derived from the CV-1 cell line by transformation with a replication origin defective mutant of SV40 VIRUS, which codes for wild type large T antigen (ANTIGENS, POLYOMAVIRUS TRANSFORMING). They are used for transfection and cloning. (The CV-1 cell line was derived from the kidney of an adult male African green monkey (CERCOPITHECUS AETHIOPS).)Sequence Alignment: The arrangement of two or more amino acid or base sequences from an organism or organisms in such a way as to align areas of the sequences sharing common properties. The degree of relatedness or homology between the sequences is predicted computationally or statistically based on weights assigned to the elements aligned between the sequences. This in turn can serve as a potential indicator of the genetic relatedness between the organisms.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.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.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.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.Isoproterenol: Isopropyl analog of EPINEPHRINE; beta-sympathomimetic that acts on the heart, bronchi, skeletal muscle, alimentary tract, etc. It is used mainly as bronchodilator and heart stimulant.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.Transducin: A heterotrimeric GTP-binding protein that mediates the light activation signal from photolyzed rhodopsin to cyclic GMP phosphodiesterase and is pivotal in the visual excitation process. Activation of rhodopsin on the outer membrane of rod and cone cells causes GTP to bind to transducin followed by dissociation of the alpha subunit-GTP complex from the beta/gamma subunits of transducin. The alpha subunit-GTP complex activates the cyclic GMP phosphodiesterase which catalyzes the hydrolysis of cyclic GMP to 5'-GMP. This leads to closure of the sodium and calcium channels and therefore hyperpolarization of the rod cells. EC 3.6.1.-.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.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.GTP Phosphohydrolases: Enzymes that hydrolyze GTP to GDP. EC 3.6.1.-.Focal Adhesion Kinase 1: A non-receptor protein tyrosine kinase that is localized to FOCAL ADHESIONS and is a central component of integrin-mediated SIGNAL TRANSDUCTION PATHWAYS. Focal adhesion kinase 1 interacts with PAXILLIN and undergoes PHOSPHORYLATION in response to adhesion of cell surface integrins to the EXTRACELLULAR MATRIX. Phosphorylated p125FAK protein binds to a variety of SH2 DOMAIN and SH3 DOMAIN containing proteins and helps regulate CELL ADHESION and CELL MIGRATION.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.Apoptosis: 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.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.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.Epidermal Growth Factor: A 6-kDa polypeptide growth factor initially discovered in mouse submaxillary glands. Human epidermal growth factor was originally isolated from urine based on its ability to inhibit gastric secretion and called urogastrone. Epidermal growth factor exerts a wide variety of biological effects including the promotion of proliferation and differentiation of mesenchymal and EPITHELIAL CELLS. It is synthesized as a transmembrane protein which can be cleaved to release a soluble active form.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.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.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.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.Phosphoserine: The phosphoric acid ester of serine.HEK293 Cells: A cell line generated from human embryonic kidney cells that were transformed with human adenovirus type 5.Myosin-Light-Chain Kinase: An enzyme that phosphorylates myosin light chains in the presence of ATP to yield myosin-light chain phosphate and ADP, and requires calcium and CALMODULIN. The 20-kDa light chain is phosphorylated more rapidly than any other acceptor, but light chains from other myosins and myosin itself can act as acceptors. The enzyme plays a central role in the regulation of smooth muscle contraction.Macromolecular Substances: Compounds and molecular complexes that consist of very large numbers of atoms and are generally over 500 kDa in size. In biological systems macromolecular substances usually can be visualized using ELECTRON MICROSCOPY and are distinguished from ORGANELLES by the lack of a membrane structure.Focal Adhesion Protein-Tyrosine Kinases: A family of non-receptor, PROLINE-rich protein-tyrosine kinases.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.GTP-Binding Protein alpha Subunits, G12-G13: A ubiquitously expressed family of heterotrimeric GTP-binding protein alpha subunits that signal through interactions with a variety of second messengers as GTPASE-ACTIVATING PROTEINS; GUANINE NUCLEOTIDE EXCHANGE FACTORS; and HEAT SHOCK PROTEINS. The G12-G13 part of the name is also spelled G12/G13.Brassica: A plant genus of the family Cruciferae. It contains many species and cultivars used as food including cabbage, cauliflower, broccoli, Brussel sprouts, kale, collard greens, MUSTARD PLANT; (B. alba, B. junica, and B. nigra), turnips (BRASSICA NAPUS) and rapeseed (BRASSICA RAPA).Electrophoresis, Polyacrylamide Gel: Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.Receptor, trkB: A protein-tyrosine kinase receptor that is specific for BRAIN-DERIVED NEUROTROPHIC FACTOR; NEUROTROPHIN 3; neurotrophin 4 and neurotrophin 5. It is widely expressed in nervous tissue and plays a role in mediating the effects of neurotrophins on growth and differentiation of neuronal cells.Janus Kinase 2: A Janus kinase subtype that is involved in signaling from GROWTH HORMONE RECEPTORS; PROLACTIN RECEPTORS; and a variety of CYTOKINE RECEPTORS such as ERYTHROPOIETIN RECEPTORS and INTERLEUKIN RECEPTORS. Dysregulation of Janus kinase 2 due to GENETIC TRANSLOCATIONS have been associated with a variety of MYELOPROLIFERATIVE DISORDERS.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.Eye ProteinsCell 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.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.Aluminum Compounds: Inorganic compounds that contain aluminum as an integral part of the molecule.Receptors, Opioid, mu: A class of opioid receptors recognized by its pharmacological profile. Mu opioid receptors bind, in decreasing order of affinity, endorphins, dynorphins, met-enkephalin, and leu-enkephalin. They have also been shown to be molecular receptors for morphine.GTPase-Activating Proteins: Proteins that activate the GTPase of specific GTP-BINDING PROTEINS.Ligands: A molecule that binds to another molecule, used especially to refer to a small molecule that binds specifically to a larger molecule, e.g., an antigen binding to an antibody, a hormone or neurotransmitter binding to a receptor, or a substrate or allosteric effector binding to an enzyme. Ligands are also molecules that donate or accept a pair of electrons to form a coordinate covalent bond with the central metal atom of a coordination complex. (From Dorland, 27th ed)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.MAP Kinase Kinase Kinase 1: A 195-kDa MAP kinase kinase kinase with broad specificity for MAP KINASE KINASES. It is found localized in the CYTOSKELETON and can activate a variety of MAP kinase-dependent pathways.Cytosol: Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.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 enzymesRibosomal 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.Receptors, Adrenergic, alpha-2: A subclass of alpha-adrenergic receptors found on both presynaptic and postsynaptic membranes where they signal through Gi-Go G-PROTEINS. While postsynaptic alpha-2 receptors play a traditional role in mediating the effects of ADRENERGIC AGONISTS, the subset of alpha-2 receptors found on presynaptic membranes signal the feedback inhibition of NEUROTRANSMITTER release.Cholestanols: Cholestanes substituted in any position with one or more hydroxy groups. They are found in feces and bile. In contrast to bile acids and salts, they are not reabsorbed.G Protein-Coupled Inwardly-Rectifying Potassium Channels: A family of inwardly-rectifying potassium channels that are activated by PERTUSSIS TOXIN sensitive G-PROTEIN-COUPLED RECEPTORS. GIRK potassium channels are primarily activated by the complex of GTP-BINDING PROTEIN BETA SUBUNITS and GTP-BINDING PROTEIN GAMMA SUBUNITS.Adrenergic beta-Agonists: Drugs that selectively bind to and activate beta-adrenergic receptors.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.Mice, Inbred C57BLStructure-Activity Relationship: The relationship between the chemical structure of a compound and its biological or pharmacological activity. Compounds are often classed together because they have structural characteristics in common including shape, size, stereochemical arrangement, and distribution of functional groups.Androstadienes: Derivatives of the steroid androstane having two double bonds at any site in any of the rings.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.Peptide Mapping: Analysis of PEPTIDES that are generated from the digestion or fragmentation of a protein or mixture of PROTEINS, by ELECTROPHORESIS; CHROMATOGRAPHY; or MASS SPECTROMETRY. The resulting peptide fingerprints are analyzed for a variety of purposes including the identification of the proteins in a sample, GENETIC POLYMORPHISMS, patterns of gene expression, and patterns diagnostic for diseases.Gene Expression Regulation, Plant: Any of the processes by which nuclear, cytoplasmic, or intercellular factors influence the differential control of gene action in plants.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)Protein Conformation: The characteristic 3-dimensional shape of a protein, including the secondary, supersecondary (motifs), tertiary (domains) and quaternary structure of the peptide chain. PROTEIN STRUCTURE, QUATERNARY describes the conformation assumed by multimeric proteins (aggregates of more than one polypeptide chain).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.Guanosine Diphosphate: A guanine nucleotide containing two phosphate groups esterified to the sugar moiety.Cyclic GMP-Dependent Protein Kinases: A group of cyclic GMP-dependent enzymes that catalyze the phosphorylation of SERINE or THREONINE residues of proteins.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.Cercopithecus aethiops: A species of CERCOPITHECUS containing three subspecies: C. tantalus, C. pygerythrus, and C. sabeus. They are found in the forests and savannah of Africa. The African green monkey (C. pygerythrus) is the natural host of SIMIAN IMMUNODEFICIENCY VIRUS and is used in AIDS research.Two-Hybrid System Techniques: Screening techniques first developed in yeast to identify genes encoding interacting proteins. Variations are used to evaluate interplay between proteins and other molecules. Two-hybrid techniques refer to analysis for protein-protein interactions, one-hybrid for DNA-protein interactions, three-hybrid interactions for RNA-protein interactions or ligand-based interactions. Reverse n-hybrid techniques refer to analysis for mutations or other small molecules that dissociate known interactions.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.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.Molecular Weight: The sum of the weight of all the atoms in a molecule.Flavonoids: A group of phenyl benzopyrans named for having structures like FLAVONES.MAP Kinase Kinase 2: A 44 kDa mitogen-activated protein kinase kinase with specificity for MITOGEN-ACTIVATED PROTEIN KINASE 1 and MITOGEN-ACTIVATED PROTEIN KINASE 3.Plants, Genetically Modified: PLANTS, or their progeny, whose GENOME has been altered by GENETIC ENGINEERING.
... has been shown to be an inhibitor of G protein-coupled receptor kinase 2 (GRK2). ... There is evidence to support that paroxetine selectively binds to and inhibits G protein-coupled receptor kinase 2 (GRK2). ... "Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility". ACS Chemical ... "Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine". ...
... it is regulated by Beta adrenergic receptor kinase type 1 (βARK or BARK) also called G protein coupled receptor kinase 2 (GRK2 ... but not cGMP-dependent protein kinase or Protein Kinase G (PKG). Furthermore, ... concluded that there are light sensing receptors, melanopsin receptors, are present in blood vessels and mediate wavelength ... and involves vascular hyperpolarization and this receptor pathway could be targeted for wavelength-specific light-based therapy ...
... downregulation of α2 adrenergic receptors is caused by the upregulation of the enzyme Adrenal G protein coupled receptor kinase ... This upregulation of GRK2 is also accompanied by upregulation and increased production of the enzyme tyrosine hydroxylase, ... "GRK2 Up-Regulation Creates a Positive Feedback Loop for Catecholamine Production in Chromaffin Cells". Molecular Endocrinology ... all of these peptides bind to opioid receptors and produce analgesic (and other) responses. The hormones are secreted from ...
GRK2 (G-protein-coupled receptor kinase 2) D2 dopamine receptor IL1RAPL1 (interleukin-1 receptor accessory protein-like 1 ... protein) PI4KIIIβ (type III phosphatidylinositol 4-kinase β) IP3 receptor (this activity is inhibited by lithium - a drug used ... It is the Ca2+-sensing subunit of the yeast phosphatidylinositol (PtdIns)-4-OH kinase, PIK1 It binds to many proteins, some in ... NCS-1 is a member of the neuronal calcium sensor family, a class of EF hand containing calcium-myristoyl-switch proteins. NCS-1 ...
Ligand-activated DP1 also mobilizes G protein-coupled receptor kinase 2 (GRK2, also known as β-Adrenergic receptor kinase 2 [ ... The Prostaglandin D2 receptor 1 (DP1), a G protein-coupled receptor encoded by the PTGDR1 gene (also termed PTGDR), is ... is a G protein-coupled receptors that works by activating G-S proteins which in turn raises cellular cAMP levels thereby ... Prostaglandin receptors Prostanoid receptors Prostaglandin DP2 receptor Eicosanoid receptor GRCh38: Ensembl release 89: ...
"Regulation of mGlu4 metabotropic glutamate receptor signaling by type-2 G-protein coupled receptor kinase (GRK2)". Molecular ... "The metabotropic glutamate receptor 4 is internalized and desensitized upon protein kinase C activation". British Journal of ... Metabotropic glutamate receptor 4 is a protein that in humans is encoded by the GRM4 gene. Together with GRM6, GRM7 and GRM8 it ... Enz R (Mar 2002). "The actin-binding protein Filamin-A interacts with the metabotropic glutamate receptor type 7". FEBS Letters ...
"Phosphorylation of the N-formyl peptide receptor carboxyl terminus by the G protein-coupled receptor kinase, GRK2". The Journal ... C5a receptor of debated function which has the structure of a G protein coupled receptor but fails to couple to G proteins. ... This gene encodes a G protein-coupled receptor cell surface protein that binds and is activated by N-Formylmethionine- ... Formyl peptide receptor 1 (FPR1, FPR1 receptor, fMet-Leu-Phe receptor 1, FMLP receptor 1, or N-formylmethionyl-leucyl- ...
Over the last two decades Koch has investigated the novel roles that G protein-coupled receptor kinases (GRKs) play in cardiac ... Particularly, preclinical studies have shown that the inhibition of GRK2 in the heart via a gene therapy approach, has led to ... Walter J. "Wally" Koch (born March 2, 1961) is an American scientist best known for his work with G protein-coupled receptors ... It was under the mentorship of Lefkowitz that Koch established a foundation in G protein-coupled receptor signaling and ...
Evron T, Daigle TL, Caron MG (March 2012). "GRK2: multiple roles beyond G protein-coupled receptor desensitization". Trends ... G protein-coupled receptor kinases (GRKs, GPCRKs) are a family of protein kinases that regulate the activity of G protein- ... Ma L, Gao J, Chen X (2005). "G Protein-Coupled Receptor Kinases". In Devi LA. The G Protein-Coupled Receptors Handbook ( ... "G Protein-Coupled Kinases and Desensitization of Receptors". In Bernstein G, Tatsuya H. G protein-coupled receptors. Boca Raton ...
It commonly occurs with G protein-coupled receptors where it is mediated by the G protein-coupled receptor kinases (GRK) and ... see Adrenergic receptor#β receptors]. β-Blockade and direct inhibition of GRK2 restores β-adrenergic receptor signaling and has ... This commonly occurs with G protein coupled receptors (see Protein kinase C#Function); cytokine and other non-G protein couple ... Similarly, single nucleotide polymorphisms in GRK4γ or that cause an increase in G protein-coupled receptor kinase (GRK) ...
G protein-coupled receptor kinase 2 (GRK2), which phosphorylates and deactivates certain G protein coupled receptors . When the ... Hata JA, Koch WJ (August 2003). "Phosphorylation of G protein-coupled receptors: GPCR kinases in heart disease". Molecular ... "Cellular expression of the carboxyl terminus of a G protein-coupled receptor kinase attenuates G beta gamma-mediated signaling ... "Role of beta gamma subunits of G proteins in targeting the beta-adrenergic receptor kinase to membrane-bound receptors". ...
G protein GIT1, GNAQ, PDE6G, PRKCB1 and Src. G protein G protein-coupled receptor kinases Kinase GRCh38: Ensembl release 89: ... Day PW, Carman CV, Sterne-Marr R, Benovic JL, Wedegaertner PB (August 2003). "Differential interaction of GRK2 with members of ... link c-Src and G-protein-coupled receptor kinase 2 in a signaling unit that regulates p42/p44 mitogen-activated protein kinase ... a G protein-coupled receptor kinase-associated ADP ribosylation factor GTPase-activating protein". Proc. Natl. Acad. Sci. U.S.A ...
Lefkowitz RJ (1998). "G protein-coupled receptors. III. New roles for receptor kinases and beta-arrestins in receptor signaling ... "GRK2 and beta-arrestin 1 as negative regulators of thyrotropin receptor-stimulated response". Mol. Endocrinol. 10 (9): 1138-46 ... "Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2 ... arrestin protein family are thought to participate in agonist-mediated desensitization of G protein-coupled receptors and cause ...
G protein)-coupled receptor kinase subfamily of the Ser/Thr protein kinase family. The protein phosphorylates the activated ... and catalytically inactive forms of GRK2 and GRK6 fails to alter the agonist-induced phosphorylation of the C5a receptor (CD88 ... 2002). "G protein-coupled receptor kinases, beta-arrestin-2 and associated regulatory proteins in the human brain: postmortem ... 1998). "β2-Adrenergic receptor regulation by GIT1, a G protein-coupled receptor kinase-associated ADP ribosylation factor ...
... activated DP2 also mobilizes G protein-coupled receptor kinases (GRKs, GRK2, GRK3, and/or GRK6) and Arrestin-2 (also termed ... G-protein coupled receptor signaling pathway. • adenylate cyclase-inhibiting G-protein coupled receptor signaling pathway. • G- ... prostaglandin D receptor activity. • G-protein coupled receptor activity. • prostaglandin J receptor activity. • prostaglandin ... coupled to cyclic nucleotide second messenger. • chemotaxis. • positive regulation of G-protein coupled receptor protein ...
Guanine nucleotide-binding proteins are a family of heterotrimeric proteins that couple cell surface, 7-transmembrane domain ... GNAQ has been shown to interact with: Beta adrenergic receptor kinase, Bruton's tyrosine kinase, RGS16, RGS4 RIC8A, and Sodium- ... Day PW, Carman CV, Sterne-Marr R, Benovic JL, Wedegaertner PB (August 2003). "Differential interaction of GRK2 with members of ... "Interaction of the G-protein G11alpha with receptors and phosphoinositidase C: the contribution of G-protein palmitoylation and ...
RKIP has also been shown to inhibit G protein coupled receptor kinases (GRK) when phosphorylated by protein kinase C. Via this ... Lorenz K, Lohse MJ, Quitterer U (2003): Protein kinase C switches the Raf kinase inhibitor from Raf-1 to GRK-2. Nature 426: 574 ... The Raf kinase inhibitor protein (RKIP) is a kinase inhibitor protein, that regulates many signaling pathways within the cell. ... Odabaei, G.; Chatterjee, D.; Jazirehi, A. R.; Goodglick, L.; Yeung, K.; Bonavida, B. (2004). "Raf-1 Kinase Inhibitor Protein: ...
Smoothened seems to be a functionally divergent member of the G protein coupled receptor super family. Other similarities ... The steps leading to Ci protein proteolysis include phosphorylation of Ci protein by several protein kinases; PKA, GSK3β and ... Arrestin 2 and GRK2". Science. 306 (5705): 2257-60. doi:10.1126/science.1104135. PMID 15618519. Alcedo, Joy; Zou, Yu; Noll, ... The Drosophila protein Fused (Fu in Figure 3) is a protein kinase that binds to Costal-2. Fused can inhibit Suppressor of Fused ...
... is a Class Frizzled (Class F) G protein-coupled receptor that is a component of the hedgehog signaling pathway and ... Aikin RA, Ayers KL, Thérond PP (April 2008). "The role of kinases in the Hedgehog signalling pathway". EMBO Reports. 9 (4): 330 ... "Activity-dependent internalization of smoothened mediated by beta-arrestin 2 and GRK2". Science. 306 (5705): 2257-60. doi: ... "Frizzled Receptors: SMO". IUPHAR Database of Receptors and Ion Channels. International Union of Basic and Clinical Pharmacology ...
G protein-coupled receptor kinase. DN-GRK2. dominant negative form of GRK2. G protein. guanine nucleotide-binding regulatory ... Sequestration of Human Muscarinic Acetylcholine Receptor hm1-hm5 Subtypes: Effect of G Protein-Coupled Receptor Kinases GRK2, ... Sequestration of Human Muscarinic Acetylcholine Receptor hm1-hm5 Subtypes: Effect of G Protein-Coupled Receptor Kinases GRK2, ... Sequestration of Human Muscarinic Acetylcholine Receptor hm1-hm5 Subtypes: Effect of G Protein-Coupled Receptor Kinases GRK2, ...
GPCR signaling is mediated by agonist-promoted interactions of GPCRs with heterotrimeric G proteins, GPCR kinases (GRKs), and ... studies reveal that 5-HIAA functions to inhibit egg laying in a manner dependent on the 5-HT receptor SER-1 and the G protein ... G protein-coupled receptors (GPCRs) regulate many animal behaviors. ... Wang, J., Luo, J., Aryal, D. K., Wetsel, W. C., Nass, R., & Benovic, J. L. (2017). G protein-coupled receptor kinase-2 (GRK-2) ...
G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in ... G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in ... G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in ... G protein-coupled receptor (GPCR) ; Egg laying ; Monoamine oxidase ; Protein kinase ; Serotonin ; Signal transduction ...
GRK2, G protein-coupled receptor kinase 2; HSC, hepatic stellate cell; HTBF, hepatic tissue blood flow; L-NAME, N-nitro-L- ... G protein-coupled receptor kinase 2-mediated phosphorylation of ezrin is required for G protein-coupled receptor-dependent ... by G protein-coupled receptor kinase 2 (GRK2).21 However, the molecular mechanisms underlying defective eNOS signaling in liver ... Inhibition of Rho-kinase leads to rapid activation of phosphatidylinositol 3-kinase/protein kinase Akt and cardiovascular ...
Wild-type (PTHR) or C terminally truncated (T480), and wild-type (GRK2) receptor and kinase-inactive (GRK2-K220R) GRK2 were ... G protein-coupled receptor kinase;. HA,. hemagglutinin;. PTH,. parathyroid hormone;. PKA,. protein kinase A;. PKC,. protein ... and protein kinase C (PKC) or by G protein-coupled receptor kinases (GRKs) (5), second sequestration of receptors from the cell ... binding of G protein-coupled receptor kinases (GRKs) to receptors, receptor phosphorylation, kinase dissociation, and finally ...
... including G protein-coupled receptor kinase 2 (GRK2), which phosphorylates G protein-coupled receptors and promotes uncoupling ... including G protein-coupled receptor kinase 2 (GRK2), which phosphorylates G protein-coupled receptors and promotes uncoupling ... including G protein-coupled receptor kinase 2 (GRK2), which phosphorylates G protein-coupled receptors and promotes uncoupling ... including G protein-coupled receptor kinase 2 (GRK2), which phosphorylates G protein-coupled receptors and promotes uncoupling ...
... guanylate kinase; GPCR, G protein-coupled receptor; GRK-2, G protein-coupled receptor kinase-2; HE, hematoxylin-eosin; INL, ... Protein kinase A (PKA) and G protein-coupled receptor kinase-2 (GRK-2) have both been shown to contribute to phosducin ... 2000 ) Phosphorylation of phosducin and phosducin-like protein by G protein-coupled receptor kinase 2. J. Biol. Chem.275, 29724 ... Santini, F., Gaidarov, I., and Keen, J. H. (2002 ) G protein-coupled receptor/arrestin3 modulation of the endocytic machinery. ...
100762552 Grk2; G protein-coupled receptor kinase 2 100761290 Adrbk2; beta-adrenergic receptor kinase 2 100768536 Kcnj3; ... 100766006 Prkca; protein kinase C alpha 100760922 Prkcb; protein kinase C beta 100762950 Prkcg; protein kinase C gamma ... 100766006 Prkca; protein kinase C alpha 100760922 Prkcb; protein kinase C beta 100762950 Prkcg; protein kinase C gamma ... 100766006 Prkca; protein kinase C alpha 100760922 Prkcb; protein kinase C beta 100762950 Prkcg; protein kinase C gamma ...
Mutations K220R in GRK2 and 3, as well as K216M/K217M () in GRK4, K415 in GRK5 (), and K215M/K216M in GRK 6() yield kinase-dead ... G protein-coupled receptor kinases: more than just kinases and not only for GPCRs.. Gurevich EV1, Tesmer JJ, Mushegian A, ... G protein-coupled receptor kinases: more than just kinases and not only for GPCRs ... G protein-coupled receptor kinases: more than just kinases and not only for GPCRs ...
GRK2. G protein-coupled receptor kinase 2. I/R. ischemia/reperfusion. i.t.. intratracheal(ly). MFG-E8. milk fat globule- ... Monocyte chemoattractant protein-1-induced CCR2B receptor desensitization mediated by the G protein-coupled receptor kinase 2. ... G protein-coupled receptor kinase 2 (GRK2): mechanisms of regulation and physiological functions. FEBS Lett. 430: 37-40. ... CXCR2 and G protein-coupled receptor kinase 2 expressions in neutrophils were measured by flow cytometry. Following LPS ...
GRK2: G protein-coupled receptor kinase 2; BL: Burkitt Lymphoma; SCID: severe combined immunodeficiency; IRG: interferon ... A KSHV microRNA Directly Targets G Protein-Coupled Receptor Kinase 2 to Promote the Migration and Invasion of Endothelial Cells ... interleukin-1 receptor-associated kinase 1; MYD88: myeloid differentiation primary response protein 88; TLR: Toll-like receptor ... protein kinase R; dsRBD: double-stranded RNA-binding domain; EBNA: Epstein-Barr nuclear antigen; LMP: Latent Membrane Protein; ...
Rabbit polyclonal GRK2 (phospho S29) antibody. Validated in WB, ELISA, IHC and tested in Mouse, Human. Cited in 1 publication(s ... G protein coupled receptor kinase 2 antibody. *G-protein coupled receptor kinase 2 antibody ... Belongs to the protein kinase superfamily. AGC Ser/Thr protein kinase family. GPRK subfamily.. Contains 1 AGC-kinase C-terminal ... Proteins and Peptides. Proteomics tools. Agonists, activators, antagonists and inhibitors. Lysates. Multiplex Assays. By ...
G protein-coupled receptor kinase 2 (GRK2) in migration and inflammation.. Penela P, Murga C, Ribas C, Salcedo A, Jurado-Pueyo ... acts as an adaptor protein in protein kinase C zeta (PKCzeta)-mediated ERK5 activation by G protein-coupled receptors (GPCR). ... Involvement of G protein-coupled receptor kinase 2 (GRK2) in the development of non-alcoholic steatosis and steatohepatitis in ... G protein-coupled receptor kinase 2 (GRK2) as an integrative signalling node in the regulation of cardiovascular function and ...
S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs) 1-5, ... It is produced by the phosphorylation of sphingosine by sphingosine kinases (SphKs) and exported out of cells via transporters ... GRK2: guanine nucleotide-binding protein-coupled receptor kinase-2; KLF2: Krüppel-like factor 2. ... As a G protein-coupled receptor, S1PR2 couples to Gi/o, Gq, and G12, and G13, as opposed to S1PR1, which couples solely to Gi/o ...
Evron T, Daigle TL, Caron MG (March 2012). "GRK2: multiple roles beyond G protein-coupled receptor desensitization". Trends ... G protein-coupled receptor kinases (GRKs, GPCRKs) are a family of protein kinases that regulate the activity of G protein- ... Ma L, Gao J, Chen X (2005). "G Protein-Coupled Receptor Kinases". In Devi LA. The G Protein-Coupled Receptors Handbook ( ... "G Protein-Coupled Kinases and Desensitization of Receptors". In Bernstein G, Tatsuya H. G protein-coupled receptors. Boca Raton ...
GRK2. G protein-coupled receptor kinase 2. MMK-1. Leu-Glu-Ser-Ile-Phe-Arg-Ser-Leu-Leu-Phe-Arg-Val-Met. NET. neutrophil ... Furthermore, LPS-induced induction of G protein-coupled receptor kinase 2 (GRK2) and down-regulation of CXCR2 are markedly ... and G protein-coupled receptor kinase 2 (GRK2) has been reported to phosphorylate CXCR2 (Angus et al., 2001). We tested the ... The proteins at the liquid interface were collected and dried using speed-Vac. Then proteins were separated by SDS-PAGE and ...
... both associated with G protein-coupled receptor (GPCR) functions and the recepto ... This collection explores up-to-date descriptions of known G protein-coupled receptor kinase (GRK)-dependent mechanisms, ... Cell-Type Specific GRK2 Interactomes: Pathophysiological Implications Federico Mayor Jr., Rocío Vila-Bedmar, Laura Nogués, ... Molecular Basis for Targeting, Inhibition, and Receptor Phosphorylation in the G Protein-Coupled Receptor Kinase 4 Subfamily ...
G protein-coupled receptor kinase GRK2 is a phospholipid-dependent enzyme that is conditionally activated by G protein beta- ... 1996 "G protein-coupled receptor kinase GRK2 is a phospholipid-dependent enzyme that is conditionally activated by G protein ... "Lipid-mediated regulation of G protein-coupled receptor kinases GRK2 & GRK3", International Symposium of Muscarinic Receptor ... 1995 "Lipid mediated regulation of G protein-coupled receptor kinases GRK2 and GRK3", Graduate Research Symposium, Society for ...
... and ASTRAL compendium for protein structure and sequence analysis ... Compound: g-protein coupled receptor kinase 2. Species: Homo ... Gene: ADRBK1, BARK, BARK1, GRK2. Database cross-references and differences (RAF-indexed): *Uniprot P25098 Domains in SCOPe 2.04 ... Description: Human G Protein-Coupled Receptor Kinase 2 in Complex with Soluble Gbetagamma Subunits and Paroxetine. Class: ... Keywords: Inhibitor complex, Protein kinase, Beta propeller, RGS homology domain, Pleckstrin homology domain, Kinase, Signal ...
Internalization of the receptors may involve G protein-coupled receptor kinase 2 (GRK2). PDEγ is a substrate for GRK2, and ... EGF receptors are tyrosine kinase growth factor receptors, and the thrombin receptor is a G protein-coupled receptor (GPCR). ... stimulated or thrombin-stimulated phosphorylation of the p44 and p42 mitogen-activated protein kinases (p42MAPK and p44MAPK). ... Internalization of both receptor tyrosine kinases and GPCRs may be important for efficient MAPK activation. ...
Invitrogen Anti-GRK2 Polyclonal, Catalog # PA5-27480. Tested in Western Blot (WB), Immunofluorescence (IF), Immunocytochemistry ... protein kinase activity protein serine/threonine kinase activity G-protein coupled receptor kinase activity protein binding ATP ... beta-AR kinase-1; Beta-ARK-1; EC 220.127.116.11; G-protein coupled receptor kinase 2; G-protein-coupled receptor kinase 2; grk 2 ... G protein-coupled receptor kinases (GRKs) are important regulators of G protein-coupled receptors(GPCRs). GRK2 (83 kDa), one of ...
Paroxetine has been shown to be an inhibitor of G protein-coupled receptor kinase 2 (GRK2). ... There is evidence to support that paroxetine selectively binds to and inhibits G protein-coupled receptor kinase 2 (GRK2). ... "Paroxetine is a direct inhibitor of g protein-coupled receptor kinase 2 and increases myocardial contractility". ACS Chemical ... "Structure-Based Design of Highly Selective and Potent G Protein-Coupled Receptor Kinase 2 Inhibitors Based on Paroxetine". ...
GRK2. G protein-coupled receptor kinase 2. GIRK. G protein-gated K+ channel. GTPγS. guanosine 5′-O-(3-thio)triphosphate.. ... 2010) The effect of protein kinase C and G protein-coupled receptor kinase inhibition on tolerance induced by μ-opioid agonists ... 2009b) Role of PKCα and G-protein-coupled receptor kinase 2 in agonist-selective desensitization of μ-opioid receptors in ... 1998) Agonist-induced homologous desensitization of μ-opioid receptors mediated by G protein-coupled receptor kinases is ...
G protein-coupled receptor kinase 2) for IHC, WB. Anti-GRK2 mAb (GTX30211) is tested in Human, Rat, Bovine samples. 100% Ab- ... G protein-coupled receptor kinase 2. Background. The product of this gene phosphorylates the beta-2-adrenergic receptor and ... Abnormal coupling of beta-adrenergic receptor to G protein is involved in the pathogenesis of the failing heart. [provided by ... enzyme that specifically phosphorylates the activated form of the beta-adrenergic and related G-protein-coupled receptors. ...
Next-day shipping cDNA ORF clones derived from GRK2 G protein-coupled receptor kinase 2 available at GenScript, starting from $ ... General protein information. Preferred Names. G protein-coupled receptor kinase 2. Names. beta-adrenergic receptor kinase 1. ... GRK2 ( NM_001619.4 ) cDNA ORF clone, Homo sapiens(human) -, NP_001610.2 Homo sapiens G protein-coupled receptor kinase 2 (GRK2 ... GRK2 ( NM_001619.3 ) cDNA ORF clone, Homo sapiens(human) -, NP_001610.2 Homo sapiens G protein-coupled receptor kinase 2 (GRK2 ...
DesensitizationSerineTyrosine kinasesBindsMitogen-activatSignalingINHIBITORRegulatesPathwayInhibitsIntracellularLigandsArrestinsSubstratesTherapeuticActivateRegulatoryOverexpressionCAMP-dependIntrinsic tyrosine kinase activityMechanismsEnzymeAgonist-occupiedSpecificityHigh affinityDownstreamResiduesGRK3StimulationPurified recombinant human GRK2EndothelialRoleGene cDNA ORF clonePeptidePleckstrinCardiovascularSubfamilyAntibodyVitroEndogenousGRK4Growth factor receptorsCell surface rActivityFunctionalMembranePromotes
- For the large family of G protein-coupled receptors ( 3 , 4 ) several mechanisms occurring at the receptor level are known to be involved in desensitization. (pnas.org)
- Agonist-induced desensitization of the PTH receptor is a well-established phenomenon ( 17 - 20 ). (pnas.org)
- Specifically phosphorylates the agonist-occupied form of the beta-adrenergic and closely related receptors, probably inducing a desensitization of them. (abcam.com)
- The product of this gene phosphorylates the beta-2-adrenergic receptor and appears to mediate agonist-specific desensitization observed at high agonist concentrations. (genetex.com)
- Evron T, Daigle TL, Caron MG (2012) GRK2: multiple roles beyond G protein-coupled receptor desensitization. (springer.com)
- Conclusion- GRK5 attenuates atherosclerosis through multiple cell type-specific mechanisms, including reduction of SMC and endothelial cell NF-κB activity and desensitization of receptor-specific signaling through the monocyte CC chemokine receptor-2, macrophage CSF-1R, and the SMC platelet-derived growth factor receptor-β. (ahajournals.org)
- Agonist-stimulated PKA-mediated phosphorylation of GRK2 may represent a mechanism for enhancing receptor phosphorylation and desensitization. (caltech.edu)
- Desensitization in response to GRK-mediated phosphorylation involves the binding of arrestin proteins that serve to sterically uncouple the receptor from its G protein. (scielo.br)
- Shortly following exposure to an agonist, GPCR responsiveness wanes as the consequence of receptor desensitization. (scielo.br)
- Receptor desensitization plays an important physiological role by preventing overstimulation of GPCR signaling cascades which in the case of constitutively active mutant receptors leads to diseases such as retinal degeneration, precocious puberty and thyroid tumors (2-4). (scielo.br)
- Moreover, receptor desensitization provides a mechanism by which GPCR-mediated signals from multiple cellular or hormonal inputs can be filtered into meaningful information. (scielo.br)
- However, the up-regulation of proteins associated with GPCR desensitization has also been associated with diseases such as hypertension, congestive heart failure and drug dependence and tolerance (5-8). (scielo.br)
- Consequently, a firm understanding of how the processes of receptor activation, desensitization and resensitization are related to one another is critical to the development of strategies aimed at ameliorating GPCR-related diseases. (scielo.br)
- The desensitization of GPCR responsiveness results as the culmination of several events including: the uncoupling of receptors from their heterotrimeric G protein as the consequence of receptor phosphorylation, sequestration (endocytosis) of receptors to endosomes and down-regulation of the total cellular complement of receptors. (scielo.br)
- Drugs targeting RGS proteins can be divided into five groups: 1) potentiators of endogenous agonist function, 2) potentiators/desensitization blockers of exogenous GPCR agonists, 3) specificity enhancers of exogenous agonists, 4) antagonists of effector signaling by an RGS protein, and 5) RGS agonists. (aspetjournals.org)
- Both were discovered in the lab of the 2012 Nobel Prize in Chemistry co-laureate Robert Lefkowitz, initially as terminators of signaling from the β-adrenergic receptor (βAR), a process known as functional desensitization. (mdpi.com)
- This phosphorylation initiates receptor desensitization and internalization, which inhibits downstream signaling pathways related to cancer progression. (ijbs.com)
- This is mainly due to drug resistance, as studies that have used short- and long-term exposure to GPCR-targeting drugs have observed receptor desensitization [ 5 , 8 , 9 ]. (ijbs.com)
- Phosphorylation and desensitization of human endothelin A and B receptors. (semanticscholar.org)
- Effect of different G protein-coupled receptor kinases on phosphorylation and desensitization of the alpha1B-adrenergic receptor. (semanticscholar.org)
- Phosphorylation and desensitization of the human beta 1-adrenergic receptor. (semanticscholar.org)
- These results demonstrate for the first time that the cardiometabolic-regulatory, anti-inflammatory, and cardioprotective functions of APN are significantly impaired by GRK2-mediated AdipoR1 phosphorylative desensitization during post-MI HF development, suggesting that inhibiting GRK2-mediated AdipoR1 phosphorylation may be a novel therapeutic target, restoring APN signaling and mitigating post-MI remodeling and HF. (ahajournals.org)
- Small molecule G protein-coupled receptor kinase inhibitors attenuate GRK2-mediated desensitization of vasoconstrictor-induced arterial contractions. (le.ac.uk)
- The beta-adrenergic receptor kinase (beta ARK) phosphorylates its membrane-associated receptor substrates, such as the beta-adrenergic receptor, triggering events leading to receptor desensitization. (duke.edu)
- Receptor-specific in vivo desensitization by the G protein-coupled receptor kinase-5 in transgenic mice. (duke.edu)
- The β-adrenergic receptor (βAR) kinase (βARK1) is a G protein-coupled receptor kinase (GRK) that controls cardiac βAR signaling via receptor phosphorylation, leading to desensitization. (ahajournals.org)
- 3 The molecules involved in desensitization include the G protein-coupled receptor kinase (GRK) family, which in the heart is represented by GRK2, GRK3, GRK4, and GRK5 and the 2 β-arrestins. (ahajournals.org)
- One biomarker molecule consistently shown to be upregulated in human HF and several animal models is G protein-coupled receptor kinase-2 (GRK2), a kinase originally discovered to be involved in G protein-coupled receptor desensitization, especially β-adrenergic receptors. (ovid.com)
- These new roles of GRK2 suggest that GRK2 may be a nodal link in the myocyte, influencing both cardiac contractile function and cell metabolism and survival and contributing to HF independent of its canonical role in G protein-coupled receptor desensitization. (ovid.com)
- G-protein-coupled receptor kinase 2 (GRK2) is a member of a kinase family originally discovered for its role in the phosphorylation and desensitization of G-protein-coupled receptors. (genes2cognition.org)
- 2) We have also designed analogues of small molecules that nitrosyl ate and thereby inactivate GRK2 (G protein-coupled receptor kinase 2 that plays an essential role in many GPCR desensitization) and analyzed their effects on lipolysis of adipocytes. (nii.ac.jp)
- This antibody detects endogenous levels of GRK2 only when phosphorylated at serine 29. (abcam.com)
- Synthesized phosphopeptide derived from human GRK2 around the phosphorylation site of serine 29 (R-A-S P -K-K). (abcam.com)
- The phosphorylated serine and threonine residues act as binding sites for arrestin proteins that prevent the reassociation of the G proteins with their receptors, thereby preventing reactivation of the signaling pathway. (wikipedia.org)
- ERK phosphorylates and thus inactivates GRK2 on serine 670 in a negative feedback mechanism. (thermofisher.com)
- We show that PKA directly phosphorylates GRK2 on serine 685. (caltech.edu)
- Wild-type (WT) p53-induced phosphatase 1 (Wip1, also called PP2Cδ) is a serine/threonine protein phosphatase belonging to the type 2Cδ protein phosphatases ( 9 ). (jimmunol.org)
- Phosphorylation of insulin receptor substrate (IRS) proteins on serine residues has emerged as a key step in these control processes under both physiological and pathological conditions. (physiology.org)
- Salmonella Effector SteE Converts the Mammalian Serine/Threonine Kinase GSK3 into a Tyrosine Kinase to Direct Macrophage Polarization. (stanford.edu)
- Here, we demonstrate that SteE converts both the amino acid and substrate specificity of the host pleiotropic serine/threonine kinase GSK3. (stanford.edu)
- Subsequent studies showed that the Epi-activated β 2 AR underwent a rapid phosphorylation by G protein-coupled receptor kinase 2 (GRK2) and subsequent dephosphorylation on serine residues 355 and 356, which was critical for sufficient receptor recycling and G i coupling. (scialert.net)
- Together, our data revealed that distinct temporal phosphorylation of β 2 AR on serine 355 and 356 by GRK2 plays a critical role for dictating receptor cellular events and signaling properties induced by Epi or NE in cardiomyocytes. (scialert.net)
- A family of serine-threonine kinases that are specific for G-PROTEIN-COUPLED RECEPTORS. (curehunter.com)
- Abstract In this review, the role of tyrosine kinases in angiotensin II-mediated signal transduction pathways in vascular smooth muscle is discussed. (ahajournals.org)
- Exciting recent data show that angiotensin II directly stimulates tyrosine kinases, including pp60 c-src kinase (c-Src), focal adhesion kinase (FAK), and Janus kinases (JAK2 and TYK2). (ahajournals.org)
- Angiotensin II may activate receptor tyrosine kinases, such as Axl and platelet-derived growth factor, by as-yet-undefined autocrine mechanisms. (ahajournals.org)
- Finally, unknown tyrosine kinases may mediate tyrosine phosphorylation of Shc, Raf, and phospholipase C-γ after angiotensin II stimulation. (ahajournals.org)
- These angiotensin II-regulated tyrosine kinases appear to be required for angiotensin II effects, such as vasoconstriction, proto-oncogene expression, and protein synthesis, on the basis of studies with tyrosine kinase inhibitors. (ahajournals.org)
- In this review we will focus on signal transduction mechanisms by which angiotensin II exerts these effects, emphasizing the role of tyrosine kinases. (ahajournals.org)
- Balabanian K, Lagane B, Infantino S, Chow KY, Harriague J, Moepps B, Arenzana-Seisdedos F, Thelen M, Bachelerie F (2005) The chemokine SDF-1/CXCL12 binds to and signals through the orphan receptor RDC1 in T lymphocytes. (springer.com)
- Before beginning a larger search for compounds that would inhibit GRK2, the researchers screened a small library of approximately 2,000 compounds that contains many FDA-approved drugs as a test of their screening procedure-and found that paroxetine binds to and inhibits the activity of GRK2. (newswise.com)
- Angiotensin II binds to at least two high-affinity receptors, designated AT 1 receptor 10 11 and AT 2 receptor. (ahajournals.org)
- NGF is a neurotrophic factor critical for the survival and maintenance of sympathetic and sensory neurons, and it binds to the high-affinity tyrosine kinase receptor, TrkA, leading to its phosphorylation and the subsequent activation of PI3K/Akt/GSK3β pathways. (biomedcentral.com)
- At the cellular level, relaxin binds to the G protein-coupled receptor relaxin family peptide receptor 1 (RXFP1) to activate a variety of downstream signal transduction pathways. (usda.gov)
- found that expression of antisense for PDEγ inhibited epidermal growth factor (EGF)-stimulated or thrombin-stimulated phosphorylation of the p44 and p42 mitogen-activated protein kinases (p42 MAPK and p44 MAPK ). (sciencemag.org)
- Stimulation of Gi-coupled receptors leads to the activation of mitogen-activated protein kinases (MAP kinases). (duke.edu)
- This motif is also found in cellular signaling proteins other than endocytic components, including G protein-coupled receptor kinase 2 (GRK2), which phosphorylates G protein-coupled receptors and promotes uncoupling of receptor-G protein interaction. (elsevier.com)
- We investigated whether Rho-kinase activation is one of the molecular mechanisms involved in defective eNOS signaling in secondary biliary cirrhosis. (wiley.com)
- It generally is assumed that only the last step inhibits receptor signaling. (pnas.org)
- Competes with RALA for binding to LPAR1 thus affecting the signaling properties of the receptor. (abcam.com)
- S1P regulates diverse physiological processes by binding to specific G protein-binding receptors, S1P receptors (S1PRs) 1-5, through a process coined as "inside-out signaling. (hindawi.com)
- K. F. Wan, B. S. Sambi, M. Frame, R. Tate, N. J. Pyne, The inhibitory γ subunit of the type 6 retinal cyclic guanosine monophosphate phosphodiesterase is a novel intermediate regulating p42/p44 mitogen-activated protein kinase signaling in human embryonic kidney 293 cells. (sciencemag.org)
- For a model of G protein-coupled receptor (GPCR) activation where all agonists stabilize a single active conformation of the receptor, a close correlation between signaling outputs might be expected. (aspetjournals.org)
- G protein βγ subunits are central participants in G protein-coupled receptor signaling pathways. (pubmedcentralcanada.ca)
- Despite enormous advances since then, there remain multiple emerging and unanswered questions about the fundamental details of the biochemical roles for Gβγ in GPCR-dependent G protein activation, as well as questions about broader roles in novel signaling mechanisms, physiology and pathophysiology. (pubmedcentralcanada.ca)
- In the classical model for G protein signaling, binding of GTP results in activation of the G protein and dissociation of the Gα subunit from the Gβγ subunits ( Fig. 1A ). (pubmedcentralcanada.ca)
- Gβγ does not have a catalytic site and thus acts as a modulator of G protein signaling through regulated protein-protein interactions. (pubmedcentralcanada.ca)
- Additionally, how all these interactions are coordinated to mediate various G protein signaling processes in cells and tissues is not entirely clear. (pubmedcentralcanada.ca)
- The regulator of G protein signaling (RGS) domain of GRK2 interacts with and inhibits Gα q in vitro. (sciencemag.org)
- The βARKrgs peptide, but not endogenous GRK2, interacted with Gα q and interfered with signaling through this G protein. (sciencemag.org)
- Busillo JM, Armando S, Sengupta R, Meucci O, Bouvier M, Benovic JL (2010) Site-specific phosphorylation of CXCR4 is dynamically regulated by multiple kinases and results in differential modulation of CXCR4 signaling. (springer.com)
- Lymphocyte levels of GRK2 (betaARK1) mirror changes in the LVAD-supported failing human heart: lower GRK2 associated with improved beta-adrenergic signaling after mechanical unloading. (semanticscholar.org)
- Targeting GPCR-Gβγ-GRK2 signaling as a novel strategy for treating cardiorenal pathologies. (semanticscholar.org)
- Considering that long-term synaptic plasticity is generally induced by short-lasting synaptic activity, regenerative mechanisms such as the positive feedback loop may be a common way to fill in the temporal gap between transient synaptic signaling and long-lasting kinase activities. (jneurosci.org)
- GRK2ct, a peptide inhibitor of GRK2 (last 194 amino acids of GRK2) is effective at rescuing models of HF through its restoration of cardiac βAR signaling. (ahajournals.org)
- βAR signaling is compromised in hypertension, likely due in part to elevated GRK2 expression, and our data suggest restoration of VSM βAR signaling by GRK2ct might be a beneficial therapeutic strategy in hypertension. (ahajournals.org)
- The regulator of G protein signaling (RGS) proteins form a recently identified protein family, and they strongly modulate the activity of G proteins. (aspetjournals.org)
- Their best known function is to inhibit G protein signaling by accelerating GTP hydrolysis [GTPase activating protein (GAP)] thus turning off G protein signals. (aspetjournals.org)
- The regulator of G protein signaling (RGS) proteins modulate the activity of G proteins in vitro, and evidence is beginning to emerge on their role in vivo as well. (aspetjournals.org)
- The RGS proteins were discovered in genetic studies of GPCR signaling pathways in model organisms ( Dohlman and Thorner, 1997 ). (aspetjournals.org)
- Adrenergic receptors on cardiac fibroblasts were manipulated to examine the role of arrestin in the spatiotemporal regulation of extracellular signal-regulated kinase (ERK)1/2 MAPK signaling. (ahajournals.org)
- Activation of Gq coupled-receptor signaling leads to prolonged ERK1/2 MAPK phosphorylation, nuclear accumulation, and cellular proliferation. (ahajournals.org)
- Interestingly, coactivation of these receptors with the β-adrenergic receptors induced transient ERK signaling localized within the cytosol, which attenuated cell proliferation. (ahajournals.org)
- One potential nexus for GPCR signaling crosstalk are the multifunctional scaffold proteins known as arrestins. (ahajournals.org)
- Arrestins not only scaffold proteins for the activation of different MAPK families under single receptor activation, but also mediate transactivation of epidermal growth factor receptor signaling pathways 2,6 and activation of many other non-GPCR signaling cascades. (ahajournals.org)
- They are now known to switch GPCR signaling from G protein-dependent to G protein-independent, which, in the case of βARs and angiotensin II type 1 receptor (AT 1 R), might be beneficial, e.g., anti-apoptotic, for the heart. (mdpi.com)
- GPCR signaling generally results in the transmission of amplified signals throughout the cell, and hyperactivation of these receptors may result in loss of normal cell physiological properties. (ijbs.com)
- Upon ligand-dependent receptor activation, GRK phosphorylates its target GPCR to prevent excessive cellular signaling. (ijbs.com)
- Stimuli, such as photons, small chemicals, ions, or protein ligands induce conformational changes in GPCR, which translates into cell signaling responses by activating coupled trimeric G protein complexes [ 15 ]. (ijbs.com)
- Cardiac alpha1-adrenergic receptors: novel aspects of expression, signaling mechanisms, physiologic function, and clinical importance. (semanticscholar.org)
- β-adrenergic receptor-mediated cardiac contractility is inhibited via vasopressin type 1A-receptor-dependent signaling. (semanticscholar.org)
- Our work shows that the organization of cholesterol in the ciliary membrane can be modified by extracellular ligands to control the activity of cilia-localized signaling proteins. (stanford.edu)
- Here, we determine whether APN receptors 1 and 2 (AdipoR1/AdipoR2, the 7-transmembrane domain-containing receptors mediating APN actions) are phosphorylatively modified post-MI, similar to G-protein coupled receptors (GPCR), impeding APN signaling. (ahajournals.org)
- Cardiac-specific GRK2 knockdown virtually abolished post-MI AdipoR1 phosphorylation, whereas virus-mediated GRK2 overexpression significantly phosphorylated AdipoR1 and blocked APN metabolic-regulatory/anti-inflammatory signaling. (ahajournals.org)
- The current study focuses on investigating the roles of these two proteins in regulating G protein signaling under the normal and hypertensive states. (uwo.ca)
- Angiotensin II and vasopressin were used to examine the effects of GRK2 on G q coupled GPCR signaling. (uwo.ca)
- On the other hand, using arborization and wrinkle assays, I have shown that GRK2 acts as a negative regulator of G s signaling in VSMCs. (uwo.ca)
- Overall, these investigations suggest that altering GRK2 expression is able to regulate both G q and G s signaling in VSMCs. (uwo.ca)
- Ligand-promoted translocation of a given receptor protein from the plasma membrane into the cell interior thus represents a key cellular pathway of GPCR signaling. (jneurosci.org)
- Intracellular mGluR5a signaling is also regulated by its association with a wide variety of intracellular regulation proteins. (biomedcentral.com)
- Group I metabotropic glutamate receptors, (mGluR1 and mGluR5), regulate excitatory synaptic signaling response via their coupling to the heterotrimeric G protein, Gα q/11 , which upon activation stimulates the activity of the enzyme phospholipase C to generate the production of two second messengers, diacylglycerol and inositol 1, 4, 5 trisphosphate. (biomedcentral.com)
- Group I mGluRs serve as molecular scaffold proteins to regulate both extracellular and intracellular signaling complexes. (biomedcentral.com)
- Contributing to these detrimental changes is a signaling molecule, G protein-coupled receptor kinase 2 (GRK2), which following ischemia accumulates in mitochondria, the energy-producing powerhouses of cells. (sciencecodex.com)
- In future studies we may be able to delineate how Western diet influences cardiac disease as it pertains to GRK2 signaling," Sato added. (sciencecodex.com)
- We have previously shown that second-messenger-dependent kinases (cAMP-dependent kinase, protein kinase C) in the olfactory system are essential in terminating second-messenger signaling in response to odorants. (duke.edu)
- Arrestin regulates almost all G protein-coupled receptor (GPCR)-mediated signaling and trafficking. (sciencemag.org)
- The signaling and trafficking of these receptors are regulated in multifaceted ways by arrestins ( 1 ). (sciencemag.org)
- Insulin signaling at target tissues is essential for growth and development and for normal homeostasis of glucose, fat, and protein metabolism. (physiology.org)
- A variety of agents and conditions that induce insulin resistance, such as TNFα and free fatty acids, activate a number of protein kinases that target elements along the insulin-signaling pathway. (physiology.org)
- Ser/Thr phosphorylation of IRS proteins inhibits their function and interferes with insulin signaling in a number of ways ( Fig. 1 ), thus leading to the development of an insulin resistance state. (physiology.org)
- Three major signaling pathways are propagated in response to activation of the IRK: phosphatidylinositol 3-kinase (PI3K), MAP kinase, and the Cbl/CAP pathway ( 92 ). (physiology.org)
- Tyr-phosphorylated IRS proteins, the major insulin receptor substrates, function as signaling scaffolds that propagate insulin action through binding of Src homology 2 (SH2) domain-containing proteins. (physiology.org)
- In the present study, to clarify the factor characterizing Stx1a gene expression via the protein kinase A (PKA) pathway inducing the Stx1a mRNA, we investigated whether the epigenetic process is involved in the Stx1a gene transcription induced by PKA signaling. (medworm.com)
- GRK2 deficiency in endothelial cells (ECs) leads to increased pro-inflammatory signaling and promotes recruitment of leukocytes to activated ECs. (portlandpress.com)
- The physiological role of phosphorylation sites and the extensive dimerization interface mediated by the regulator of G protein signaling (RGS) homology domain of GRK1 was assessed using site-directed mutagenesis. (utexas.edu)
- Many Gram-negative bacterial pathogens antagonize anti-bacterial immunity through translocated effector proteins that inhibit pro-inflammatory signaling. (stanford.edu)
- Overall, the conversion of GSK3 to a tyrosine-directed kinase representsa tightly regulated event that enables a bacterial virulence protein to reprogram innate immune signaling and establish an anti-inflammatory environment. (stanford.edu)
- Agonist-dependent activation of G protein-coupled receptors induces diversified receptor cellular and signaling properties. (scialert.net)
- This study not only helps us understand the endogenous agonist-dependent β 2 AR signaling in animal heart but also offers an example of how G protein-coupled receptor signaling may be finely regulated by GRK in physiological settings. (scialert.net)
- Recently, nonclassical roles for GRK2 in cardiovascular disease have been described, including negative regulation of insulin signaling, a role in myocyte cell survival and apoptotic signaling, and it has been shown to be localized in/on mitochondria. (ovid.com)
- Thus, understanding angiotensin II-stimulated signaling events, especially those related to tyrosine kinase activity, may form the basis for the development of new therapies for cardiovascular diseases. (ahajournals.org)
- 12 To date, the signal transduction pathways activated by the AT 2 receptor remain unknown, so this review will focus on AT 1 signaling. (ahajournals.org)
- An important downstream signaling pathway activated by Rho GTPases are Rho kinases (ROKs). (duke.edu)
- Recently we identified the serotonin reuptake inhibitor paroxetine as an inhibitor of G protein-coupled receptor kinase 2 (GRK2) that improves cardiac performance in live animals. (rcsb.org)
- John Tesmer, research professor at the U-M Life Sciences Institute and professor in the Department of Pharmacology at the U-M Medical School, and his research team at the Tesmer lab found that paroxetine, a selective serotonin reuptake inhibitor (SSRI) sold under the name Paxil, inhibits G protein-coupled receptor kinase 2 (GRK2), a protein kinase that becomes over-expressed when people have heart failure. (newswise.com)
- The paper, "Paroxetine is a Direct Inhibitor of G Protein-Coupled Receptor Kinase 2 and Increases Myocardial Contractility," was published electronically ahead of print on Aug. 21 in ACS Chemical Biology . (newswise.com)
- Overexpression of the cardiac beta(2)-adrenergic receptor and expression of a beta-adrenergic receptor kinase-1 (betaARK1) inhibitor both increase myocardial contractility but have differential effects on susceptibility to ischemic injury. (duke.edu)
- Functionally active targeting domain of the beta-adrenergic receptor kinase: an inhibitor of G beta gamma-mediated stimulation of type II adenylyl cyclase. (duke.edu)
- I've been trying to find a GRK2 inhibitor for 20 years. (temple.edu)
- G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabo" by Jianjun Wang, Jiansong Luo et al. (jefferson.edu)
- G protein-coupled receptor kinase-2 (GRK-2) regulates serotonin metabolism through the monoamine oxidase AMX-2 in Caenorhabditis elegans. (jefferson.edu)
- We aimed to characterize the cellular mechanism by which GPCR crosstalk regulates mitogen-activated protein kinase (MAPK) activation. (ahajournals.org)
- GRK2 becomes increasingly expressed as the system that regulates normal heartbeat and the strength of the heart's contractions weakens. (newswise.com)
- CaMKIIα positively regulates both mGluR1a and mGluR5a endocytosis, but selectively attenuates mGluR5a but not mGluR1a-stimulated ERK1/2 phosphorylation in a kinase activity-dependent manner. (biomedcentral.com)
- However, a second pathway in which proteins are directly modified by NO addition to sulfhydryl residues, a process known as S-nitrosylation (SNO), has recently emerged in the scientific literature. (frontiersin.org)
- Although PKG activation pathway has been largely involved in NO-mediated cardioprotection ( 11 - 13 ), SNO is now taking the front stage and is considered to be a key player in cardioprotection through (i) the transient modification of protein activity and/or (ii) their protection from irreversible oxidation ( 14 - 17 ). (frontiersin.org)
- Thus, stabilization of off-pathway conformational states unique to GRK2 will likely be key for the development of even more selective inhibitors. (rcsb.org)
- TLRs recognize molecules derived from microbes and are thus members of the pathogen recognition receptor surveillance pathway. (physiology.org)
- 7 In the case of GPCR-induced extracellular signal-regulated kinase (ERK) mitogen-activated protein kinase (MAPK) activation, both G proteins and arrestins are capable of mediating ERK activation via independent mechanisms, with each pathway leading to unique spatiotemporal consequences. (ahajournals.org)
- Real-time trafficking of the sst 2A receptor was also examined in regard to key proteins of the endocytic pathway, clathrin and β-arrestins 1 and 2. (jneurosci.org)
- Our results further identify TLR4-induced NF-κB1p105-ERK pathway to be selectively regulated by GRK2. (genes2cognition.org)
- The ability of GRK-phosphorylated receptors to activate G proteins is essentially normal, but the binding of β-arrestins to the phosphorylated receptors inhibits G protein activation by receptors ( 10 , 11 ). (pnas.org)
- Arrestin2 directly or through GRK2 inhibits PKC?II activation in a ubiquitination-dependent manner. (genscript.com)
- GRK2 inhibits TNFalpha-induced ERK activation by inhibiting generation of reactive oxygen species. (genscript.com)
- A particular part of the kinase and scaffolding protein GRK2 inhibits a G protein that promotes cardiac hypertrophy. (sciencemag.org)
- To test this hypothesis, we used a mutant form of RKIP that is not phosphorylated by PKC and thus constitutively inhibits Raf-1 and MEK, upstream kinases of MAPK. (jneurosci.org)
- GRK2 siRNA inhibits the increase of PGE2-induced HUVECs migration and tube formation. (portlandpress.com)
- Activation of a GPCR results in the modulation of intracellular second messenger levels and/or ionic conductances via the coupling of receptors to a wide variety of effector systems via heterotrimeric guanine nucleotide-binding proteins (G proteins). (scielo.br)
- Vasoconstrictor-driven G protein-coupled receptor (GPCR)/phospholipase C (PLC) signalling increases intracellular Ca2+ concentration to mediate arterial contraction. (le.ac.uk)
- In the present study, we utilized mass spectroscopy to identify calmodulin kinase IIα (CaMKIIα) as a protein that interacts with the second intracellular loop domain of mGluR5. (biomedcentral.com)
- Arrestin interacts with the predicted third intracellular (3i) loop of α 2 -adrenergic receptor (AR) subtypes ( 6 - 8 ) that also interacts with spinophilin ( 7 ). (sciencemag.org)
- Inaddition, the intracellular pathogen Salmonella enterica serovar Typhimurium initiates an anti-inflammatorytranscriptional response in macrophages through its effector protein SteE. (stanford.edu)
- Hedgehog ligands increase cholesterol accessibility in the membrane of the primary cilium by inactivating the transporter-like protein Patched 1. (stanford.edu)
- Alterations in the signalling of growth factors (VEGF) and chemiokins (ligands of GPCR receptors coupled to G proteins), may condition the clinical development of HHT. (fundacionareces.es)
- In particular, G protein-coupled receptor kinase 2 interacts with a diverse repertoire of non-GPCR substrates. (wikipedia.org)
- The encoded protein phosphorylates the beta-adrenergic receptor as well as a wide range of other substrates including non-GPCR cell surface receptors, and cytoskeletal, mitochondrial, and transcription factor proteins. (genscript.com)
- Two of the α 2 AR subtypes, the α 2A AR and α 2B AR, are substrates for GRK2-catalyzed phosphorylation ( 7 , 13 ) and phosphorylation-dependent arrestin binding. (sciencemag.org)
- Binding of insulin to its receptor activates the intrinsic tyrosine kinase activity of the receptor (IRK), which phosphorylates Tyr residues of target proteins such as the insulin receptor substrates (IRS-1 to -6), Shc proteins, Cbl, p60dok, APS, and Gab-1 ( 92 , 112 ). (physiology.org)
- These data support the development of GRK2-based therapeutic approaches to prevent hypertrophy and heart failure. (sciencemag.org)
- The results of these studies show that inhibiting GRK2 is a viable therapeutic approach that reduces acute ischemia injury to the myocardium, and is a strategy to limit acute myocardial ischemia. (redorbit.com)
- Now, a Temple-led research team shows for the first time that blocking GRK2 localization to mitochondria protects heart cells from ischemic injury and death, casting new light on GRK2 as a potential therapeutic target in post-injury heart failure. (sciencecodex.com)
- The last therapeutic strategy aimed to act on brain insulin resistance, which is one of the pathological features found in MSA patient brains, through viral-mediated overexpression of a micro RNA that reduces the expression of the G protein (heterotrimeric guanine nucleotide-binding protein)-coupled receptor kinase 2 (GRK2). (archives-ouvertes.fr)
- After stimulation with the agonist norepinephrine, 1 both βARs activate adenylyl cyclase via coupling to the heterotrimeric G protein G s , stimulating the production of the second messenger, cAMP. (ahajournals.org)
- Based on these structures, a model is proposed for how GRK1 interacts with activated rhodopsin and how rhodopsin binding in turn could activate the kinase. (utexas.edu)
- The present report overviews the current understanding of GPCR regulatory mechanisms and how green fluorescent protein (GFP) from the jellyfish Aqueora victoria is facilitating this understanding. (scielo.br)
- Monitoring the nucleotide exchange in vitro, together with reconstitution of direct interactions with regulatory proteins, provides key insights into how a GTPase is activated. (stanford.edu)
- Genetic screens that use untargeted mutagenesis have the potential to identify protein-coding genes, non-coding RNAs and regulatory elements, but their analysis has mainly focused on identifying the former two. (stanford.edu)
- By blocking GRK2, an important regulatory enzyme, they cut the hormone production that forces the heart to pump too hard, leading to heart failure. (bio-medicine.org)
- They are regulatory proteins that play a role in G-protein-coupled receptor densensitization. (curehunter.com)
- Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. (duke.edu)
- Ogg P, McDonell P, Ryckman B, Knudson C, Roller R. The HSV-1 Us3 protein kinase is sufficient to block apoptosis induced by overexpression of a variety of Bcl-2 family members. (labome.org)
- Their unique feature is the specific phosphorylation of only agonist-activated G protein-coupled receptors, but they differ in tissue distribution, posttranslational modifications, and mechanisms of membrane targeting. (pnas.org)
- In this review, we focus on recent developments in the study of long and small non-protein-coding RNAs, including microRNAs, of oncogenic pathogens, and discuss their mechanisms of action in the multiple steps of oncogenesis. (bioscience.org)
- This collection explores up-to-date descriptions of known G protein-coupled receptor kinase (GRK)-dependent mechanisms, both associated with G protein-coupled receptor (GPCR) functions and the receptor-independent. (springer.com)
- GRK2 activity is tightly controlled by different mechanisms including phosphorylation by kinases such as PKC, Src and ERK1 and 2, as well as interaction with various proteins. (thermofisher.com)
- There are several mechanisms including GTP hydrolysis, second messenger related protein kinases (e.g. (ijbs.com)
- Molecular mechanisms underlying GPCR endocytosis and postendocytosis are receptor specific, may vary between cell types, and are still not clearly characterized. (jneurosci.org)
- The purpose of this study was to examine the expression levels of macrophage migration inhibitory factor (MIF) and G protein-coupled receptor kinase 2 (GRK2) in patients with early diabetic cardiomyopathy, and to investigate the mechanisms involved in MIF expression and GRK2 activation. (plos.org)
- Conversely, enhancing GRK2 expression counteracts mesenchymal cells traits by mechanisms involving phosphorylation and decreased functionality of the key EMT inducer Snail1. (bvsalud.org)
- This protein is an ubiquitous cytosolic enzyme that specifically phosphorylates the activated form of the beta-adrenergic and related G-protein-coupled receptors. (genetex.com)
- GRK2-mediated receptor phosphorylation is preceded by the agonist-dependent membrane association of this enzyme. (duke.edu)
- A beta-adrenergic receptor kinase-like enzyme is involved in olfactory signal termination. (duke.edu)
- The study by a team of scientists at Temple University School of Medicine's (TUSM) is the first to identify the molecule, an enzyme known as GRK2 (G protein-coupled receptor kinase 2), in mitochondria. (medindia.net)
- The current study grows out of Dr. Koch's two decades of investigation into an enzyme called GRK2, which stands for G protein-coupled receptor kinase-2. (temple.edu)
- In addition, GRK2 can be stimulated by binding to the agonist-occupied form of receptors. (jefferson.edu)
- The beta-adrenergic receptor kinase (beta ARK) phosphorylates the agonist-occupied beta-adrenergic receptor to promote rapid receptor uncoupling from Gs, thereby attenuating adenylyl cyclase activity. (duke.edu)
- GRK2 attenuates GPCR‐mediated signalling through phosphorylation of agonist‐occupied receptors. (bl.uk)
- The beta-adrenergic receptor kinase specifically phosphorylates the agonist-occupied form of the beta-adrenergic and related G protein-coupled receptors. (genecards.org)
- Evidence for G protein-coupled receptor kinase specificity. (semanticscholar.org)
- Monoclonal antibodies reveal receptor specificity among G-protein-coupled receptor kinases. (duke.edu)
- These receptors are classified into three subgroups based on sequence similarity and G protein coupling specificity. (biomedcentral.com)
- They interact with receptors, G protein α subunits and downstream targets to coordinate multiple, different GPCR functions. (pubmedcentralcanada.ca)
- Traditionally, activated receptors couple to G proteins, which transduce downstream signals via second messengers and membrane channels. (ahajournals.org)
- Tyr-phosphorylated IRS proteins then serve as docking molecules for downstream effectors such as PI3K and phosphotyrosine phosphatase 2 (SHP-2). (physiology.org)
- Residues Arg106 and Asp110 in GRK2/3, among others, are important for binding Gα q , a function unique to this subfamily. (nih.gov)
- Truncation and site-directed mutagenesis studies revealed that basic residues on the receptor are important for binding to GRK2. (jefferson.edu)
- Ser phosphorylation of residues located at the PH domain interferes with binding of IRS-1 to the plasma membrane and to the receptor. (physiology.org)
- phosphorylation of Ser/Thr residues within the PTB domain or at the COOH-terminal region of IRS-1 induces dissociation of IRS-1 from the receptor concomitant with IRS-1 degradation. (physiology.org)
- G protein-coupled receptor (GPCR) activation is followed rapidly by adaptive changes that serve to diminish the responsiveness of a cell to further stimulation. (scielo.br)
- The applicants have recently shown that, in the context of levodopa-induced dyskinesias, the debilitating motoric manifestation that limit the use of the best drug ever developed for Parkinson's disease, dopamine receptors are not enough internalized in response to the levodopa administration as too many remain at the membrane surface, i.e. being still available for continuing stimulation. (michaeljfox.org)
- Direct evidence that Gi-coupled receptor stimulation of mitogen-activated protein kinase is mediated by G beta gamma activation of p21ras. (duke.edu)
- In human umbilical vein endothelial cells (HUVECs), GRK2‐depletion caused a 30% reduction in WPB numbers by increasing steady‐state release of VWF. (bl.uk)
- Two of the key components of TGF-beta signalling, the specific ALK1 endothelial receptor and the co-receptor endoglin, are mutated in a high percentage of patients with Hereditary Haemorrhagic Telangiectasia (HHT or the Oslo-Weber-Rendu syndrome), causing anomalous angiogenic remodelling. (fundacionareces.es)
- In basal terms, the lack of GRK2 also gives rise to greater endothelial secretion of SDF-1α and PDGF-BB, which contribute to distorting the interaction between endothelial cells and pericytes. (fundacionareces.es)
- Conclusion]: Taken together, these results suggest a role for GRK2 in the establishment and/or development of NASH. (csic.es)
- What role do toll-like receptors (TLRs) have in ovulated cumulus-oocyte complexes (COCs)? (physiology.org)
- We also characterized the role of the extreme amino terminus of GRK2 in receptor phosphorylation. (jefferson.edu)
- 3 A pivotal role in this mechanism is played by the GRK2, better known as the βAR kinase 1 (βARK1). (ahajournals.org)
- However, the role of GRK2 in regulating angiogenesis remains unclear. (portlandpress.com)
- Further research found that Lys220 and Ser685 of GRK2 play an important role in angiogenesis by regulating GRK2 translocation. (portlandpress.com)
- Altogether, our results demonstrate that βγ subunit of heterotrimeric G proteins play a critical role in neurite outgrowth and differentiation by interacting with MTs and modulating MT rearrangement. (biomedcentral.com)
- In this paper we have analyzed the role of the most important GRK expressed in cardiovascular system (βAK 1 or GRK2) in umbilical artery (UA)of preeclamptic patients and normotensive pregnant women to characterize its eventual role in the pathogenesis of preeclampsia and related clinical syndromes, such as gestational hypertension (GH) and fetal growth restriction (FGR). (unina.it)
- Previous research by Dr. Koch and his colleagues has demonstrated the role of GRK2 in heart failure. (temple.edu)
- Synthetic phospho-peptide against the C terminal region of Human GRK2, around S685 (UniProt ID: P25098). (abcam.com)
- As shown in Figure 1 , latent TGF β is composed of a TGF β dimer in a noncovalent complex with the TGF β propeptide or latency-associated peptide (LAP) that remains bound to TGF β after secretion, retaining TGF β in an inactive form and the latent TGF β -binding protein (LTBP) which is linked to LAP by a disulfide bond [ 12 ]. (hindawi.com)
- We generated a synthetic peptide of the first 14 amino acids of GRK2. (jefferson.edu)
- In vitro, increasing concentrations of the peptide inhibited receptor phosphorylation by full-length GRK2 and enhanced phospholipid binding of GRK2. (jefferson.edu)
- Crosslinking experiments with the synthetic peptide and GRK2 suggested an intramolecular interaction between the amino terminus and the rest of GRK2. (jefferson.edu)
- The defining feature of the GRK2/3 subfamily is a C-terminal pleckstrin homology (PH) domain (blue) implicated in binding anionic phospholipids and Gβγ. (nih.gov)
- The x-ray crystal structure of the inactive form of GRK2 has been solved, revealing an equilateral triangle formed by the three main domains: RGS, kinase and pleckstrin homology domain. (jefferson.edu)
- IRS proteins contain a conserved pleckstrin homology (PH) domain at their NH 2 terminus followed by a phosphotyrosine-binding (PTB) domain. (physiology.org)
- We knew from our previous work that GRK2 accumulates in mitochondria following ischemia, but the detrimental impacts of mitochondrial pooling of GRK2 were unclear," explained Walter J. Koch, PhD, W.W. Smith Endowed Chair in Cardiovascular Medicine, Professor and Chair of the Department of Pharmacology, and Director of the Center for Translational Medicine at the Lewis Katz School of Medicine at Temple University (LKSOM) and senior investigator on the new report. (sciencecodex.com)
- Arias-Loza PA, Jazbutyte V, Pelzer T. Genetic and pharmacologic strategies to determine the function of estrogen receptor alpha and estrogen receptor beta in cardiovascular system. (springer.com)
- Because we have shown earlier that prenylation and subsequent methylation/demethylation of γ subunits are required for the Gβγ-MTs interaction in vitro , small-molecule inhibitors (L-28 and L-23) targeting prenylated methylated protein methyl esterase (PMPMEase) were tested in the current study. (biomedcentral.com)
- In particular it is well known that: (a) levels of cathecolamines are directly correlated with mortality and functional status in heart failure, (b) β 1 -adrenergic receptor subtype is down-regulated in heart failure, (c) heart failure-dependent cardiac adrenergic responsiveness reduction is related to changes in G proteins activity. (frontiersin.org)
- We hypothesize that this intramolecular interaction is necessary to stabilize the extreme amino terminus of the kinase by binding to the RGS domain of GRK2 thereby causing a conformational change in the catalytic domain and modulating the kinase activity from inactive to the active state. (jefferson.edu)
- Both of these studies show that the absence of GRK2 activity protects the cardiac myocytes against ischemic reperfusion. (redorbit.com)
- GRK2, which levels inversely correlate with the extent of α-tubulin acetylation in epithelial cells and fibroblasts, directly associates with and phosphorylates HDAC6 to stimulate α-tubulin deacetylase activity. (sebbm.es)
- They also plan to search for proteins that might interact with GRK2 within the mitochondria to determine whether the detrimental effects of GRK2 are due to kinase activity or to a scaffolding effect that involves multiple proteins. (sciencecodex.com)
- We have known that GRK2 is involved in the pathological development of certain heart diseases, such as chronic heart failure, and that its increased activity can lead to the death of heart cells. (medindia.net)
- These data suggest that enhancing GRK2 activity in bone forming OBs reduces bone mass. (duke.edu)
- But the test run discovered that the antidepressant both bound GRK2 and inhibited its activity. (temple.edu)
- Heart failure is accompanied by severely impaired beta-adrenergic receptor (betaAR) function, which includes loss of betaAR density and functional uncoupling of remaining receptors. (duke.edu)
- The nuclear receptor ERRα is required for the bioenergetic and functional adaptation to cardiac pressure overload. (springer.com)
- Functional selectivity of agonists has gained increasing interest in G protein-coupled receptor (GPCR) research, e.g. due to expectations of drugs with reduced adverse effects. (usda.gov)
- The protein kinase A-anchoring protein AKAP79 influences beta 2AR phosphorylation by complexing PKA with the receptor at the membrane. (caltech.edu)
- Koch's team found that in ischemic heart cells the movement of GRK2 from the cell membrane to mitochondria is chaperoned by a substance called heat-shock protein 90 (Hsp90), which is produced in cells in response to stress. (medindia.net)
- G Protein-coupled Receptor Kinase 2 (GRK2) Promotes Breast Tumorigenesis Through a HDAC6-Pin1 Axis. (nih.gov)
- Title: Long noncoding RNA UCA1 promotes tumour metastasis by inducing GRK2 degradation in gastric cancer. (genscript.com)
- The DLK-1 kinase promotes mRNA stability and local translation in C. elegans synapses and axon regeneration. (duke.edu)
- The latter promotes interaction of IRS proteins with the juxtamembrane (JM) domain of the insulin receptor (IR), which phosphorylates the IRS proteins at their COOH-terminal region. (physiology.org)
- The phosphorylation of HDAC6 by GRK2 increases the deacetylation of tubulin and promotes cell spreading and migration. (fundacionareces.es)