Phosphorylation: The introduction of a phosphoryl group into a compound through the formation of an ester bond between the compound and a phosphorus moiety.Sirolimus: A macrolide compound obtained from Streptomyces hygroscopicus that acts by selectively blocking the transcriptional activation of cytokines thereby inhibiting cytokine production. It is bioactive only when bound to IMMUNOPHILINS. Sirolimus is a potent immunosuppressant and possesses both antifungal and antineoplastic properties.TOR Serine-Threonine Kinases: A serine threonine kinase that controls a wide range of growth-related cellular processes. The protein is referred to as the target of RAPAMYCIN due to the discovery that SIROLIMUS (commonly known as rapamycin) forms an inhibitory complex with TACROLIMUS BINDING PROTEIN 1A that blocks the action of its enzymatic activity.Protein Kinases: A family of enzymes that catalyze the conversion of ATP and a protein to ADP and a phosphoprotein.Protein Kinase Inhibitors: Agents that inhibit PROTEIN KINASES.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.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-Tyrosine Kinases: Protein kinases that catalyze the PHOSPHORYLATION of TYROSINE residues in proteins with ATP or other nucleotides as phosphate donors.Phosphatidylinositol 3-Kinases: Phosphotransferases that catalyzes the conversion of 1-phosphatidylinositol to 1-phosphatidylinositol 3-phosphate. Many members of this enzyme class are involved in RECEPTOR MEDIATED SIGNAL TRANSDUCTION and regulation of vesicular transport with the cell. Phosphatidylinositol 3-Kinases have been classified both according to their substrate specificity and their mode of action within the cell.Enzyme Activation: Conversion of an inactive form of an enzyme to one possessing metabolic activity. It includes 1, activation by ions (activators); 2, activation by cofactors (coenzymes); and 3, conversion of an enzyme precursor (proenzyme or zymogen) to an active enzyme.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.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.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.Phosphatidylethanolamine Binding Protein: A ubiquitously found basic protein that binds to phosphatidylethanolamine and NUCLEOTIDES. It is an endogenous inhibitor of RAF KINASES and may play a role in regulating SIGNAL TRANSDUCTION. Phosphatidylethanolamine-binding protein is the precursor of hippocampal cholinergic neurostimulating peptide, which is cleaved from the N-terminal region of the protein.PhosphoproteinsCell Line: Established cell cultures that have the potential to propagate indefinitely.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.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.QuinolinesCell Line, Tumor: A cell line derived from cultured tumor cells.Immunosuppressive Agents: Agents that suppress immune function by one of several mechanisms of action. Classical cytotoxic immunosuppressants act by inhibiting DNA synthesis. Others may act through activation of T-CELLS or by inhibiting the activation of HELPER CELLS. While immunosuppression has been brought about in the past primarily to prevent rejection of transplanted organs, new applications involving mediation of the effects of INTERLEUKINS and other CYTOKINES are emerging.Proto-Oncogene Proteins c-akt: A protein-serine-threonine kinase that is activated by PHOSPHORYLATION in response to GROWTH FACTORS or INSULIN. It plays a major role in cell metabolism, growth, and survival as a core component of SIGNAL TRANSDUCTION. Three isoforms have been described in mammalian cells.Mutation: Any detectable and heritable change in the genetic material that causes a change in the GENOTYPE and which is transmitted to daughter cells and to succeeding generations.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.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.Kinetics: The rate dynamics in chemical or physical systems.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.Antineoplastic Agents: Substances that inhibit or prevent the proliferation of NEOPLASMS.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.Tyrosine: A non-essential amino acid. In animals it is synthesized from PHENYLALANINE. It is also the precursor of EPINEPHRINE; THYROID HORMONES; and melanin.Cell Proliferation: All of the processes involved in increasing CELL NUMBER including CELL DIVISION.Substrate Specificity: A characteristic feature of enzyme activity in relation to the kind of substrate on which the enzyme or catalytic molecule reacts.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)Cell Cycle: The complex series of phenomena, occurring between the end of one CELL DIVISION and the end of the next, by which cellular material is duplicated and then divided between two daughter cells. The cell cycle includes INTERPHASE, which includes G0 PHASE; G1 PHASE; S PHASE; and G2 PHASE, and CELL DIVISION PHASE.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)Antibiotics, Antineoplastic: Chemical substances, produced by microorganisms, inhibiting or preventing the proliferation of neoplasms.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 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.Imidazoles: Compounds containing 1,3-diazole, a five membered aromatic ring containing two nitrogen atoms separated by one of the carbons. Chemically reduced ones include IMIDAZOLINES and IMIDAZOLIDINES. Distinguish from 1,2-diazole (PYRAZOLES).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.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.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.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.Xenograft Model Antitumor Assays: In vivo methods of screening investigative anticancer drugs, biologic response modifiers or radiotherapies. Human tumor tissue or cells are transplanted into mice or rats followed by tumor treatment regimens. A variety of outcomes are monitored to assess antitumor effectiveness.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.Carrier Proteins: Transport proteins that carry specific substances in the blood or across cell membranes.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.Phosphoserine: The phosphoric acid ester of serine.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).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.Cyclin-Dependent Kinase Inhibitor p27: A cyclin-dependent kinase inhibitor that coordinates the activation of CYCLIN and CYCLIN-DEPENDENT KINASES during the CELL CYCLE. It interacts with active CYCLIN D complexed to CYCLIN-DEPENDENT KINASE 4 in proliferating cells, while in arrested cells it binds and inhibits CYCLIN E complexed to CYCLIN-DEPENDENT KINASE 2.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.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.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.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.Binding Sites: The parts of a macromolecule that directly participate in its specific combination with another molecule.Mitogen-Activated Protein Kinase 3: A 44-kDa extracellular signal-regulated MAP kinase that may play a role the initiation and regulation of MEIOSIS; MITOSIS; and postmitotic functions in differentiated cells. It phosphorylates a number of TRANSCRIPTION FACTORS; and MICROTUBULE-ASSOCIATED PROTEINS.Cyclic 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.PhosphopeptidesElectrophoresis, Polyacrylamide Gel: Electrophoresis in which a polyacrylamide gel is used as the diffusion medium.Okadaic Acid: A specific inhibitor of phosphoserine/threonine protein phosphatase 1 and 2a. It is also a potent tumor promoter. (Thromb Res 1992;67(4):345-54 & Cancer Res 1993;53(2):239-41)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.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.Molecular Weight: The sum of the weight of all the atoms in a molecule.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.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.Recombinant Proteins: Proteins prepared by recombinant DNA technology.Tetradecanoylphorbol Acetate: A phorbol ester found in CROTON OIL with very effective tumor promoting activity. It stimulates the synthesis of both DNA and RNA.Base Sequence: The sequence of PURINES and PYRIMIDINES in nucleic acids and polynucleotides. It is also called nucleotide sequence.Cell Cycle Proteins: Proteins that control the CELL DIVISION CYCLE. This family of proteins includes a wide variety of classes, including CYCLIN-DEPENDENT KINASES, mitogen-activated kinases, CYCLINS, and PHOSPHOPROTEIN PHOSPHATASES as well as their putative substrates such as chromatin-associated proteins, CYTOSKELETAL PROTEINS, and TRANSCRIPTION FACTORS.Cyclin-Dependent Kinase Inhibitor p21: A cyclin-dependent kinase inhibitor that mediates TUMOR SUPPRESSOR PROTEIN P53-dependent CELL CYCLE arrest. p21 interacts with a range of CYCLIN-DEPENDENT KINASES and associates with PROLIFERATING CELL NUCLEAR ANTIGEN and CASPASE 3.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.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.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.Time Factors: Elements of limited time intervals, contributing to particular results or situations.Protein Processing, Post-Translational: Any of various enzymatically catalyzed post-translational modifications of PEPTIDES or PROTEINS in the cell of origin. These modifications include carboxylation; HYDROXYLATION; ACETYLATION; PHOSPHORYLATION; METHYLATION; GLYCOSYLATION; ubiquitination; oxidation; proteolysis; and crosslinking and result in changes in molecular weight and electrophoretic motility.Ribosomal Protein S6 Kinases, 70-kDa: A family of ribosomal protein S6 kinases that are considered the major physiological kinases for RIBOSOMAL PROTEIN S6. Unlike RIBOSOMAL PROTEIN S6 KINASES, 90KDa the proteins in this family are sensitive to the inhibitory effects of RAPAMYCIN and contain a single kinase domain. They are referred to as 70kDa proteins, however ALTERNATIVE SPLICING of mRNAs for proteins in this class also results in 85kDa variants being formed.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.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.Dose-Response Relationship, Drug: The relationship between the dose of an administered drug and the response of the organism to the drug.Models, Biological: Theoretical representations that simulate the behavior or activity of biological processes or diseases. For disease models in living animals, DISEASE MODELS, ANIMAL is available. Biological models include the use of mathematical equations, computers, and other electronic equipment.Pyrimidines: A family of 6-membered heterocyclic compounds occurring in nature in a wide variety of forms. They include several nucleic acid constituents (CYTOSINE; THYMINE; and URACIL) and form the basic structure of the barbiturates.Phosphotransferases (Alcohol Group Acceptor): A group of enzymes that transfers a phosphate group onto an alcohol group acceptor. EC 2.7.1.Staurosporine: An indolocarbazole that is a potent PROTEIN KINASE C inhibitor which enhances cAMP-mediated responses in human neuroblastoma cells. (Biochem Biophys Res Commun 1995;214(3):1114-20)Isoenzymes: Structurally related forms of an enzyme. Each isoenzyme has the same mechanism and classification, but differs in its chemical, physical, or immunological characteristics.DNA-Binding Proteins: Proteins which bind to DNA. The family includes proteins which bind to both double- and single-stranded DNA and also includes specific DNA binding proteins in serum which can be used as markers for malignant diseases.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.Ethers, Cyclic: Compounds of the general formula R-O-R arranged in a ring or crown formation.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.Polyenes: Hydrocarbons with more than one double bond. They are a reduced form of POLYYNES.Protein Phosphatase 1: A eukayrotic protein serine-threonine phosphatase subtype that dephosphorylates a wide variety of cellular proteins. The enzyme is comprised of a catalytic subunit and regulatory subunit. Several isoforms of the protein phosphatase catalytic subunit exist due to the presence of multiple genes and the alternative splicing of their mRNAs. A large number of proteins have been shown to act as regulatory subunits for this enzyme. Many of the regulatory subunits have additional cellular functions.Cell Division: The fission of a CELL. It includes CYTOKINESIS, when the CYTOPLASM of a cell is divided, and CELL NUCLEUS DIVISION.Phosphothreonine: The phosphoric acid ester of threonine. Used as an identifier in the analysis of peptides, proteins, and enzymes.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.ChromonesOxidative Phosphorylation: Electron transfer through the cytochrome system liberating free energy which is transformed into high-energy phosphate bonds.Androstadienes: Derivatives of the steroid androstane having two double bonds at any site in any of the rings.Maximum Tolerated Dose: The highest dose of a biologically active agent given during a chronic study that will not reduce longevity from effects other than carcinogenicity. (from Lewis Dictionary of Toxicology, 1st ed)HeLa Cells: The first continuously cultured human malignant CELL LINE, derived from the cervical carcinoma of Henrietta Lacks. These cells are used for VIRUS CULTIVATION and antitumor drug screening assays.MorpholinesCarcinoma, Renal Cell: A heterogeneous group of sporadic or hereditary carcinoma derived from cells of the KIDNEYS. There are several subtypes including the clear cells, the papillary, the chromophobe, the collecting duct, the spindle cells (sarcomatoid), or mixed cell-type carcinoma.Transcription Factors: Endogenous substances, usually proteins, which are effective in the initiation, stimulation, or termination of the genetic transcription process.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.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.Mitochondria, Heart: The mitochondria of the myocardium.Kidney Neoplasms: Tumors or cancers of the KIDNEY.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.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.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.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.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.Genistein: An isoflavonoid derived from soy products. It inhibits PROTEIN-TYROSINE KINASE and topoisomerase-II (DNA TOPOISOMERASES, TYPE II); activity and is used as an antineoplastic and antitumor agent. Experimentally, it has been shown to induce G2 PHASE arrest in human and murine cell lines and inhibits PROTEIN-TYROSINE KINASE.Cell Nucleus: Within a eukaryotic cell, a membrane-limited body which contains chromosomes and one or more nucleoli (CELL NUCLEOLUS). The nuclear membrane consists of a double unit-type membrane which is perforated by a number of pores; the outermost membrane is continuous with the ENDOPLASMIC RETICULUM. A cell may contain more than one nucleus. (From Singleton & Sainsbury, Dictionary of Microbiology and Molecular Biology, 2d ed)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.Phosphorus Radioisotopes: Unstable isotopes of phosphorus that decay or disintegrate emitting radiation. P atoms with atomic weights 28-34 except 31 are radioactive phosphorus isotopes.Mutagenesis, Site-Directed: Genetically engineered MUTAGENESIS at a specific site in the DNA molecule that introduces a base substitution, or an insertion or deletion.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.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.Ribosomal Protein S6 Kinases, 90-kDa: A family of ribosomal protein S6 kinases that are structurally distinguished from RIBOSOMAL PROTEIN S6 KINASES, 70-KDA by their apparent molecular size and the fact they contain two functional kinase domains. Although considered RIBOSOMAL PROTEIN S6 KINASES, members of this family are activated via the MAP KINASE SIGNALING SYSTEM and have been shown to act on a diverse array of substrates that are involved in cellular regulation such as RIBOSOMAL PROTEIN S6 and CAMP RESPONSE ELEMENT-BINDING PROTEIN.PiperazinesProton-Translocating ATPases: Multisubunit enzymes that reversibly synthesize ADENOSINE TRIPHOSPHATE. They are coupled to the transport of protons across a membrane.Cyclins: A large family of regulatory proteins that function as accessory subunits to a variety of CYCLIN-DEPENDENT KINASES. They generally function as ENZYME ACTIVATORS that drive the CELL CYCLE through transitions between phases. A subset of cyclins may also function as transcriptional regulators.Pyridines: Compounds with a six membered aromatic ring containing NITROGEN. The saturated version is PIPERIDINES.Tumor Suppressor Proteins: Proteins that are normally involved in holding cellular growth in check. Deficiencies or abnormalities in these proteins may lead to unregulated cell growth and tumor development.Cytosol: Intracellular fluid from the cytoplasm after removal of ORGANELLES and other insoluble cytoplasmic components.Flavonoids: A group of phenyl benzopyrans named for having structures like FLAVONES.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.Nuclear Proteins: Proteins found in the nucleus of a cell. Do not confuse with NUCLEOPROTEINS which are proteins conjugated with nucleic acids, that are not necessarily present in the nucleus.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 enzymesMAP 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.Transcription, Genetic: The biosynthesis of RNA carried out on a template of DNA. The biosynthesis of DNA from an RNA template is called REVERSE TRANSCRIPTION.Models, Molecular: Models used experimentally or theoretically to study molecular shape, electronic properties, or interactions; includes analogous molecules, computer-generated graphics, and mechanical structures.Fibroblasts: Connective tissue cells which secrete an extracellular matrix rich in collagen and other macromolecules.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.Protein Phosphatase 2: A phosphoprotein phosphatase subtype that is comprised of a catalytic subunit and two different regulatory subunits. At least two genes encode isoforms of the protein phosphatase catalytic subunit, while several isoforms of regulatory subunits exist due to the presence of multiple genes and the alternative splicing of their mRNAs. Protein phosphatase 2 acts on a broad variety of cellular proteins and may play a role as a regulator of intracellular signaling processes.Isoquinolines: A group of compounds with the heterocyclic ring structure of benzo(c)pyridine. The ring structure is characteristic of the group of opium alkaloids such as papaverine. (From Stedman, 25th ed)Receptor Protein-Tyrosine Kinases: A class of cellular receptors that have an intrinsic PROTEIN-TYROSINE KINASE activity.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).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.Multiprotein Complexes: Macromolecular complexes formed from the association of defined protein subunits.Benzamides: BENZOIC ACID amides.NF-kappa B: Ubiquitous, inducible, nuclear transcriptional activator that binds to enhancer elements in many different cell types and is activated by pathogenic stimuli. The NF-kappa B complex is a heterodimer composed of two DNA-binding subunits: NF-kappa B1 and relA.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.Rabbits: The species Oryctolagus cuniculus, in the family Leporidae, order LAGOMORPHA. Rabbits are born in burrows, furless, and with eyes and ears closed. In contrast with HARES, rabbits have 22 chromosome pairs.Antineoplastic Combined Chemotherapy Protocols: The use of two or more chemicals simultaneously or sequentially in the drug therapy of neoplasms. The drugs need not be in the same dosage form.Drug Administration Schedule: Time schedule for administration of a drug in order to achieve optimum effectiveness and convenience.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).Submitochondrial Particles: The various filaments, granules, tubules or other inclusions within mitochondria.Mice, Inbred C57BLCell Membrane: The lipid- and protein-containing, selectively permeable membrane that surrounds the cytoplasm in prokaryotic and eukaryotic cells.Oxazoles: Five-membered heterocyclic ring structures containing an oxygen in the 1-position and a nitrogen in the 3-position, in distinction from ISOXAZOLES where they are at the 1,2 positions.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.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.1-(5-Isoquinolinesulfonyl)-2-Methylpiperazine: A specific protein kinase C inhibitor, which inhibits superoxide release from human neutrophils (PMN) stimulated with phorbol myristate acetate or synthetic diacylglycerol.Cell Survival: The span of viability of a cell characterized by the capacity to perform certain functions such as metabolism, growth, reproduction, some form of responsiveness, and adaptability.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.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).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.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.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.QuinazolinesProtein 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.G1 Phase: The period of the CELL CYCLE preceding DNA REPLICATION in S PHASE. Subphases of G1 include "competence" (to respond to growth factors), G1a (entry into G1), G1b (progression), and G1c (assembly). Progression through the G1 subphases is effected by limiting growth factors, nutrients, or inhibitors.Nerve Tissue ProteinsProtein 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.Peptide Fragments: Partial proteins formed by partial hydrolysis of complete proteins or generated through PROTEIN ENGINEERING techniques.eIF-2 Kinase: A dsRNA-activated cAMP-independent protein serine/threonine kinase that is induced by interferon. In the presence of dsRNA and ATP, the kinase autophosphorylates on several serine and threonine residues. The phosphorylated enzyme catalyzes the phosphorylation of the alpha subunit of EUKARYOTIC INITIATION FACTOR-2, leading to the inhibition of protein synthesis.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.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.Mass Spectrometry: An analytical method used in determining the identity of a chemical based on its mass using mass analyzers/mass spectrometers.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.Cyclin-Dependent Kinase 2: A key regulator of CELL CYCLE progression. It partners with CYCLIN E to regulate entry into S PHASE and also interacts with CYCLIN A to phosphorylate RETINOBLASTOMA PROTEIN. Its activity is inhibited by CYCLIN-DEPENDENT KINASE INHIBITOR P27 and CYCLIN-DEPENDENT KINASE INHIBITOR P21.Microtubule-Associated Proteins: High molecular weight proteins found in the MICROTUBULES of the cytoskeletal system. Under certain conditions they are required for TUBULIN assembly into the microtubules and stabilize the assembled microtubules.Vanadates: Oxyvanadium ions in various states of oxidation. They act primarily as ion transport inhibitors due to their inhibition of Na(+)-, K(+)-, and Ca(+)-ATPase transport systems. They also have insulin-like action, positive inotropic action on cardiac ventricular muscle, and other metabolic effects.Focal Adhesion Protein-Tyrosine Kinases: A family of non-receptor, PROLINE-rich protein-tyrosine kinases.Aurovertins: Very toxic and complex pyrone derivatives from the fungus Calcarisporium arbuscula. They bind to and inhibit mitochondrial ATPase, thereby uncoupling oxidative phosphorylation. They are used as biochemical tools.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.DiglyceridesEpidermal 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.Nitriles: Organic compounds containing the -CN radical. The concept is distinguished from CYANIDES, which denotes inorganic salts of HYDROGEN CYANIDE.Treatment Outcome: Evaluation undertaken to assess the results or consequences of management and procedures used in combating disease in order to determine the efficacy, effectiveness, safety, and practicability of these interventions in individual cases or series.Angioedema: Swelling involving the deep DERMIS, subcutaneous, or submucosal tissues, representing localized EDEMA. Angioedema often occurs in the face, lips, tongue, and larynx.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.Gene Expression: The phenotypic manifestation of a gene or genes by the processes of GENETIC TRANSCRIPTION and GENETIC TRANSLATION.Calcium-Binding Proteins: Proteins to which calcium ions are bound. They can act as transport proteins, regulator proteins, or activator proteins. They typically contain EF HAND MOTIFS.Protein Biosynthesis: The biosynthesis of PEPTIDES and PROTEINS on RIBOSOMES, directed by MESSENGER RNA, via TRANSFER RNA that is charged with standard proteinogenic AMINO ACIDS.Calmodulin: A heat-stable, low-molecular-weight activator protein found mainly in the brain and heart. The binding of calcium ions to this protein allows this protein to bind to cyclic nucleotide phosphodiesterases and to adenyl cyclase with subsequent activation. Thereby this protein modulates cyclic AMP and cyclic GMP levels.MAP Kinase 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.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.Mitosis: A type of CELL NUCLEUS division by means of which the two daughter nuclei normally receive identical complements of the number of CHROMOSOMES of the somatic cells of the species.DNA: A deoxyribonucleotide polymer that is the primary genetic material of all cells. Eukaryotic and prokaryotic organisms normally contain DNA in a double-stranded state, yet several important biological processes transiently involve single-stranded regions. DNA, which consists of a polysugar-phosphate backbone possessing projections of purines (adenine and guanine) and pyrimidines (thymine and cytosine), forms a double helix that is held together by hydrogen bonds between these purines and pyrimidines (adenine to thymine and guanine to cytosine).Muscle Proteins: The protein constituents of muscle, the major ones being ACTINS and MYOSINS. More than a dozen accessory proteins exist including TROPONIN; TROPOMYOSIN; and DYSTROPHIN.Immunoprecipitation: The aggregation of soluble ANTIGENS with ANTIBODIES, alone or with antibody binding factors such as ANTI-ANTIBODIES or STAPHYLOCOCCAL PROTEIN A, into complexes large enough to fall out of solution.Phosphoric Monoester Hydrolases: A group of hydrolases which catalyze the hydrolysis of monophosphoric esters with the production of one mole of orthophosphate. EC 3.1.3.Alkaloids: Organic nitrogenous bases. Many alkaloids of medical importance occur in the animal and vegetable kingdoms, and some have been synthesized. (Grant & Hackh's Chemical Dictionary, 5th ed)MaleimidesI-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.Reverse Transcriptase Polymerase Chain Reaction: A variation of the PCR technique in which cDNA is made from RNA via reverse transcription. The resultant cDNA is then amplified using standard PCR protocols.Amino Acids: Organic compounds that generally contain an amino (-NH2) and a carboxyl (-COOH) group. Twenty alpha-amino acids are the subunits which are polymerized to form proteins.Up-Regulation: A positive regulatory effect on physiological processes at the molecular, cellular, or systemic level. At the molecular level, the major regulatory sites include membrane receptors, genes (GENE EXPRESSION REGULATION), mRNAs (RNA, MESSENGER), and proteins.
A protein phosphatase is a phosphatase enzyme that removes a phosphate group from the phosphorylated amino acid residue of its substrate protein. Protein phosphorylation is one of the most common forms of reversible protein posttranslational modification (PTM), with up to 30% of all proteins being phosphorylated at any given time. Protein kinases (PKs) are the effectors of phosphorylation and catalyse the transfer of a γ-phosphate from ATP to specific amino acids on proteins. Several hundred PKs exist in mammals and are classified into distinct super-families. Proteins are phosphorylated predominantly on Ser, Thr and Tyr residues, which account for 79.3, 16.9 and 3.8% respectively of the phosphoproteome, at least in mammals. In contrast, protein phosphatases (PPs) are the ...
... NA-activated also known as protein kinase R (PKR), interferon-induced, double-stranded RNA-activated protein kinase, or eukaryotic translation initiation factor 2-alpha kinase 2 (EIF2AK2) is an enzyme that in humans is encoded by the EIF2AK2 gene. PKR protects against viral infections. Protein kinase-R is activated by double-stranded RNA (dsRNA), introduced to the cells by a viral infection. PKR can also be activated by the protein PACT or by heparin. PKR contains an N-terminal dsRNA binding domain (dsRBD) and a C-terminal kinase domain, that gives it pro-apoptotic (cell-killing) functions. The dsRBD consists of two tandem copies of a conserved double stranded RNA binding motif, dsRBM1 and dsRBM2. PKR is induced by interferon in a latent state. Binding to dsRNA is believed to activate PKR by inducing dimerization and subsequent ...
MAP kinase-activated protein kinase 2 is an enzyme that in humans is encoded by the MAPKAPK2 gene. This gene encodes a member of the Ser/Thr protein kinase family. This kinase is regulated through direct phosphorylation by p38 MAP kinase. In conjunction with p38 MAP kinase, this kinase is known to be involved in many cellular processes including stress and inflammatory responses, nuclear export, gene expression regulation and cell proliferation. Heat shock protein HSP27 was shown to be one of the substrates of this kinase in vivo. Two transcript variants encoding two different isoforms have been found for this gene. SB 203580, suppresses the activation of MAPKAPK2 MAPKAPK2 has been shown to interact with: AKT1, MAPK14, PHC2, and SHC1. GRCh38: Ensembl release 89: ENSG00000162889 - Ensembl, May 2017 GRCm38: ...
Lawler OA, Miggin SM, Kinsella BT (2001). "Protein kinase A-mediated phosphorylation of serine 357 of the mouse prostacyclin receptor regulates its coupling to G(s)-, to G(i)-, and to G(q)-coupled effector signaling.". J. Biol. Chem. 276 (36): 33596-607. PMID 11443126. doi:10.1074/jbc.M104434200. ...
Activated CDC42 kinase 1, also known as ACK1, is an enzyme that in humans is encoded by the TNK2 gene. TNK2 gene encodes a non-receptor tyrosine kinase, ACK1, that binds to multiple receptor tyrosine kinases e.g. EGFR, MERTK, AXL, HER2 and insulin receptor (IR). ACK1 also interacts with Cdc42Hs in its GTP-bound form and inhibits both the intrinsic and GTPase-activating protein (GAP)-stimulated GTPase activity of Cdc42Hs. This binding is mediated by a unique sequence of 47 amino acids C-terminal to an SH3 domain. The protein may be involved in a regulatory mechanism that sustains the GTP-bound active form of Cdc42Hs and which is directly linked to a tyrosine phosphorylation signal transduction pathway. Several alternatively spliced transcript variants have been identified from this gene, but the full-length nature of only two transcript variants has been determined. ACK1 or TNK2 has been shown to interact ...
Transforming growth factor-beta (TGF-beta)[6] is a multifunctional peptide that controls proliferation, differentiation and other functions in many cell types. TGF-beta-1 is a peptide of 112 amino acid residues derived by proteolytic cleavage from the C-terminal of a precursor protein. These proteins interact with a conserved family of cell surface serine/threonine-specific protein kinase receptors, and generate intracellular signals using a conserved family of proteins called SMADs. They play fundamental roles in the regulation of basic biological processes such as growth, development, tissue homeostasis and regulation of the immune system.[3]. ...
Glycogen synthase kinase 3 is a serine/threonine protein kinase that mediates the addition of phosphate molecules onto serine and threonine amino acid residues. First discovered in 1980 as a regulatory kinase for its namesake, Glycogen synthase, GSK-3 has since been identified as a kinase for over forty different proteins in a variety of different pathways. In mammals GSK-3 is encoded by two known genes, GSK-3 alpha (GSK3A) and GSK-3 beta (GSK3B). GSK-3 has recently been the subject of much research because it has been implicated in a number of diseases, including Type II diabetes (Diabetes mellitus type 2), Alzheimer's Disease, inflammation, cancer, and bipolar disorder. GSK-3 functions by phosphorylating a serine or threonine residue on its target substrate. A positively charged pocket adjacent to the active site binds a "priming" phosphate group attached to a serine or threonine four ...
RTKs play a key role in the communication of cells with their microenvironment. These molecules are involved in the regulation of cell growth, differentiation, and metabolism. In several cases the biochemical mechanism by which RTKs transduce signals across the membrane has been shown to be ligand induced receptor oligomerization and subsequent intracellular phosphorylation. In the case of DDR2, the ligand is collagen which binds to its extracellular discoidin domain.[6] This autophosphorylation leads to phosphorylation of cytosolic targets as well as association with other molecules, which are involved in pleiotropic effects of signal transduction. DDR2 has been associated with a number of diseases including fibrosis and cancer.[7]. ...
GAD67 and GAD65 are also regulated differently post-translationally. Both GAD65 and GAD67 are regulated via phosphorylation of a dynamic catalytic loop,[10][11] but the regulation of these isoforms differs; GAD65 is activated by phosphorylation while GAD67 is inhibited by phosphorylation. GAD67 is predominantly found activated (~92%), whereas GAD65 is predominantly found inactivated (~72%).[12] GAD67 is phosphorylated at threonine 91 by protein kinase A (PKA), while GAD65 is phosphorylated, and therefore regulated by, protein kinase C (PKC). Both GAD67 and GAD65 are also regulated post-translationally by Pyridoxal 5'-phosphate (PLP); GAD is activated when bound to PLP and inactive when not bound to PLP.[12] Majority of GAD67 is bound to PLP at any given time, whereas GAD65 binds PLP when GABA is needed for neurotransmission.[12] This reflects the functional properties of the two isoforms; ...
Protein kinases, many of which are regulated by autophosphorylation, are vital in controlling the cellular proliferation, differentiation, metabolism, migration and survival. Mutations in the genes encoding them or their potential activators or repressors can affect any number of functions within an organism.[3][4] Phosphorylation is easily reversed by phosphatases. Therefore, it is an effective method of turning 'on' and 'off' kinase activity. Because of this it is recognized as an essential process in cell signaling.[3] Addition of a negatively charged phosphate group brings about a change in the microenvironment that may lead to attraction or repulsion of other residues or molecules.[3][4] The result may be a conformational change to expose or hide catalytic or allosteric seats from the surface.[3] If the phosphorylated residue resides within the catalytic seat itself, it may facilitate or prevent substrate binding by ...
Protein Tob1 is a protein that in humans is encoded by the TOB1 gene. This gene encodes a member of the tob/btg1 family of anti-proliferative proteins that have the potential to regulate cell growth. When exogenously expressed, this protein suppresses cell growth in tissue culture. The protein undergoes phosphorylation by a serine/threonine kinase, 90 kDa ribosomal S6 kinase. Interactions of this protein with the v-erb-b2 erythroblastic leukemia viral oncogene homolog 2 gene product p185 interferes with growth suppression. This protein inhibits T cell proliferation and transcription of cytokines and cyclins. The protein interacts with both mothers against decapentaplegic Drosophila homolog 2 and 4 to enhance their DNA binding activity. This interaction inhibits interleukin 2 transcription in T cells. TOB1 ...
Brill LM، Salomon AR، Ficarro SB، وآخرون. (2004). "Robust phosphoproteomic profiling of tyrosine phosphorylation sites from human T cells using immobilized metal affinity chromatography and tandem mass spectrometry.". Anal. Chem. 76 (10): 2763-72. PMID 15144186. doi:10.1021/ac035352d. الوسيط ...
Akt1通过抑制凋亡过程从而参与细胞存活途径。Akt1亦能诱导蛋白合成通路,故其在导致骨骼肌肥大及的一般组织生长的细胞通路中是一种重要信号蛋白。因其可以阻断凋亡并继而促进细胞存活,现已表明Akt1在多种肿瘤中起到主要作用。Akt(先亦被称为Akt1)首先是在转化逆转录病毒AKT8中被鉴定为癌基因的[3]。 Akt2在胰岛素信号通路中是一重要的信号分子。需要其来诱导葡萄糖转运。在敲除Akt1但具正常Akt2的小鼠中,血糖稳态不受干扰,但动物体型会较小,这与Akt1在生长中起得作用是一致的。相反,Akt2缺失但具有正常Akt1的的小鼠生长略缺陷且表现出糖尿病表型(胰岛素抵抗),这从另一方面印证了Akt2对胰岛素受体信号通路更具特异性的这一设想[4]。 Akt3似乎主要在脑中表达,但其作用仍未明晰。有报道显示Akt3缺失的小鼠脑部较小[5]。 ...
The pyruvate kinase RBC isozyme and pyruvate kinase liver isozyme are tissue-specific isoforms and are found in RBCs (pyruvate ... as the mechanistic target of rapamycin inhibitor rapamycin inhibited Hcy-induced changes in PKM2 enzyme activity and B cell ... supplemented with protease inhibitors and PMSF. Protein concentrations of the cell lysates were determined, and 2 μg of total ... Treatment with a low dose of rapamycin (10 nM) strongly suppressed phosphorylation of mTOR and its downstream target S6RP in ...
adenosine monophosphate-activated protein kinase), mTORC1/2 (mammalian target of rapamycin complexes), and STAT6 (signal ... and small molecules targeting host genes and specific bacterial species or phylum/class may help to reestablish tissue ... two small molecule inhibitors of PKM2 (pyruvate kinase isozyme 2), inhibit LPS-induced HIF-1α and IL-1β, thereby promoting the ... intermediates for the synthesis of ribose for nucleotides and amino acids for the biosynthesis by RNA and DNA of proteins by ...
Mammalian target of rapamycin is a member of the phosphoinositide kinase-like kinase family, a group of variant protein kinases ... Because protein phosphorylation regulates the activity of many proteins involved in cancer, phosphorylation-specific antibodies ... it is possible that small changes in tissue fixation procedures (e.g., inclusion of phosphatase inhibitors) would improve the ... FoxOs also enhance transcription of the cyclin-dependent kinase inhibitor p21Cip1 (13) . Finally, FoxO proteins promote ...
Effects of the mammalian target of rapamycin inhibitor CCI-779 used alone or with chemotherapy on human prostate cancer cells ... In general, AP-1 proteins have both overlapping as well as unique roles and function in a tissue- and/or cell-specific manner ... Antisense technology has been used for the development of Raf kinase selective inhibitors. The Raf kinase inhibitor ISI 5132 ... Although all Raf proteins can activate the MAPK cascade, they seem to have distinct downstream phosphorylation targets. GTP- ...
1998) Design of allele-specific inhibitors to probe protein kinase signaling. Curr Biol 8:257-266. ... We found that the in vivo level of Atg13 phosphorylation by PKA was not diminished upon rapamycin treatment (Fig. 5B). In ... 2000) A chemical switch for inhibitor-sensitive alleles of any protein kinase. Nature 407:395-401. ... including tissue remodeling during development, the removal of protein aggregates, and innate immune responses (5, 6). During ...
A third group of possible downstream signaling intermediates of PI3 kinase comprises several protein kinase C (PKC) isoforms. ... Wortmannin and LY294002 are two potent and specific inhibitors of PI3 kinase, the use of which has established a role for PI3 ... Targeted overexpression of IGF-I evokes distinct patterns of organ remodeling in smooth muscle cell tissue beds of transgenic ... IGF-I caused tyrosine phosphorylation of several major proteins, including two proteins with the apparent molecular sizes of ...
C57BL/6 mice to compare the effects of metformin and the direct mammalian target of rapamycin (mTOR) inhibitor rapamycin on PC ... Rapamycin, a specific mTOR inhibitor, inhibits several processes involved in tumor cell proliferation and survival (16,17). ... increased AMP kinase (AMPK) activity (13), and inhibition of the mammalian target of rapamycin (mTOR), a complex that couples ... The rapamycin dose of 2.5 mg/kg was chosen to achieve inhibition of phosphorylation of mTOR based on our previous studies (20 ...
3D). This compound was thought to be an inhibitor specific for phosphatidylinositol 3-kinase (PI3K), but more recently, the ... mammalian target of rapamycin) that phosphorylates Ser473 of Akt (16). Although we have not attempted to identify the target of ... Importantly, the expression of dynAP activated Akt (also known as protein kinase B) by promoting Ser473 phosphorylation ... Exploration of tissue-specific dynAP expression including cancer tissues and clarification of regulatory mechanism of its gene ...
Phosphorylation of ULK1 (hATG1) by AMP-activated protein kinase connects energy sensing to mitophagy. Science 2011;331:456-461 ... 2). These findings form the basis for the use of rapamycin, a known inhibitor of mTORC1, to activate autophagy. Studies in ... transfecting GFP-LC3 construct by in vivo electroporation or else the use of conventional GFP-LC3 and tissue-specific ... Mouse Apg16L, a novel WD-repeat protein, targets to the autophagic isolation membrane with the Apg12-Apg5 conjugate. J Cell Sci ...
... general Drug resistance Drug therapy Pharmacogenetics Pharmacogenomics Tumor proteins Tumors ... mitogen-activated protein kinase; MDR, multidrug resistance; mTOR, mammalian target of rapamycin; PI3 K, phosphoinositid-3- ... Visual Molecular Dynamics (VMD) was used to depict the docking poses of honokiol and the inhibitors for each target protein. ... Kinase inhibitor Microarrays Multidrug resistance Introduction Despite the break-taking progresses in cancer biology during the ...
MicroRNA-550a acts as a pro-metastatic gene and directly targets cytoplasmic polyadenylation element-binding protein 4 in ... Regulation of insulin-like growth factor-mammalian target of rapamycin signaling by microRNA in childhood adrenocortical tumors ... c-Src is required for tropomyosin receptor kinase C (TrkC)-induced activation of the phosphatidylinositol 3-kinase (PI3K)-AKT ... treated with mTORC1 inhibitor, cytostatic antiproliferative proline-rich polypeptide (PRP-1). Examination of tumor-specific ...
... and mTORC1 inhibition using rapamycin or mTOR kinase inhibitors AZD8055 or Torin1 increased EGFR and HER2 protein expression in ... and MiT/TFE proteins are known bonafide proteasomal substrates (55, 56) that can be targeted for degradation by phosphorylation ... and another AKT kinase inhibitor AZD5363 downregulated EGFR and HER2 protein expression in Rptor-cre (Figure 8G and ... AKT activation can increase the ubiquitination and proteasomal degradation of specific substrates (53, 54) via phosphorylation ...
The advent of PI3K-specific small molecular inhibitors has led to increased efficacy with avoidance of an excessive toxicity ... Keywords: copanlisib, follicular lymphoma, PI3K, non-Hodgkin lymphoma, kinase inhibitor ... Key enzymes of the PI3K pathway exhibit differing expression in tissue types and roles in tumor pathogenesis. Copanlisib (BAY ... pathway in cell survival and proliferation has made it an attractive target in cancer therapy. The development of small ...
In this study, we discovered that mechanical stimulation of integrin β1 leads to the phosphorylation of AKT, an event which ... Habitual mechanical loading or targeted exercise causes tendon cells to increase the stiffness of the extracellular matrix; ... thereby triggering cell signaling pathways which lead to adaptive regulation of mRNA translation and protein synthesis. ... required the presence of integrin-linked kinase (ILK). Repetitive stretching of tendon cells activates the AKT and mTOR ...
... evidenced by decreased phosphorylation of S6 Kinase, its phosphorylation target S6, and 4EBP1 31. Accordingly, we found ... Signaling by target of rapamycin proteins in cell growth control. Microbiol. Mol Biol Rev. 2005;69:79-100. [PMC free article] [ ... 5a,b). The selective mTORC1 inhibitor rapamycin pronouncedly blocked p-S6 in mouse lungs and MLF under control conditions (Fig ... context specific roles, which might lead to opposing effects in models of disease. The cell - specific (i.e., alveolar vs. ...
Activation of S6 kinase by phosphorylation, for instance, results in the subsequent phosphorylation of ribosomal protein S6 ( ... Active-site inhibitors of mTOR target rapamycin-resistant outputs of mTORC1 and mTORC2. PLoS Biol. 7, e38 (2009).. ... The small molecule rapamycin is a specific inhibitor of mTORC1, and derivatives are used clinically in cancer treatment, ... For tissue homogenization, frozen tissues were placed into the prechilled chamber of a cryogenic tissue pulverizer (RPI) and ...
How can the metabolic contributions mediated through checkpoint proteins be targeted to maximize antitumor effects? Do specific ... The mTOR kinase determines effector versus memory CD8+ T cell fate by regulating the expression of transcription factors T-bet ... Decreased expression of B7-H3 reduces the glycolytic capacity and sensitizes breast cancer cells to AKT/mTOR inhibitors. ... 1). Although glycolysis is a physiologic response to hypoxia in normal tissues, cancer cells constitutively take up glucose and ...
... the mammalian target of rapamycin (mTOR) effector p70 ribosomal S6 kinase (p70S6K), and phosphorylation of insulin receptor ... cells with saturating concentrations of the MEK-specific inhibitor U0126 and the AKT-specific inhibitor Akt inhibitor X (AKTiX ... c-Jun N-terminal kinase (JNK) signaling, and the p38 mitogen-activated protein kinase (MAPK) pathway, were unaltered or ... c-Met as a target for human cancer and characterization of inhibitors for therapeutic intervention. Cancer Lett. 225, 1-26 ( ...
Lipids take part in a variety of physiological functions and have specific roles depending on their chemical structure and ... They bind specific protein targets to elicit signalling responses in important cellular events such as growth regulation, cell ... The resulting sphingosine is phosphorylation by sphingosine kinase, producing S1P. S1P signalling interacts with histone ... an important intermediate for protein prenylation. Cholesterol also forms the structural backbone of hormone synthesis in the ...
Role of mammalian target of rapamycin, protein kinase B, and phosphatidylinositol 3-kinase in GLUT1 mRNA translation. J Biol ... Phosphorylation and activation of heart 6-phosphofructo-2-kinase by protein kinase B and other protein kinases of the insulin ... we tested the effects of the mTOR inhibitor rapamycin on anti-Ig-induced glucose uptake. In several experiments, rapamycin only ... or 20 nM rapamycin (Ig+Rap) for 30 minutes and then stimulated with 10 μg/mL anti-Ig (Ig) for 18 hours. The inhibitors had no ...
... and the protein kinase activity of PKM2 (36). Phosphorylation of PKM2 at serine-37 recruits peptidyl-prolyl cis-trans isomerase ... Mammalian target of rapamycin up-regulation of pyruvate kinase isoenzyme type M2 is critical for aerobic glycolysis and tumor ... The expression of pyruvates is tissue-specific and regulated by various promoters and alternative splicing. PKL and PKR are ... including intermediates and substrates for the synthesis of nucleotides, proteins and membrane components, which are required ...
Randomized phase II study of multiple dose levels of CCI-779, a novel mammalian target of rapamycin kinase inhibitor, in ... Rapamycin induces tumor-specific thrombosis via tissue factor in the presence of VEGF. Blood 2005;105:4463-9. ... Ribosomal protein S6 phosphorylation is a determinant of cell size and glucose homeostasis. Genes Dev 2005;19:2199-21. ... Patients in intermediate or poor-risk groups based on the clinical criteria used by Memorial Sloan-Kettering Cancer Institute ( ...
... whereas rapamycin, an inhibitor of the Akt target mTOR, did not alter the ability of insulin to phosphorylate Akt (Figure 6D). ... A specific product of phosphatidylinositol 3-kinase directly activates the protein kinase Akt through its pleckstrin homology ... A representative immunoblot of phosphorylation of Akt in response to coadministration of PI3 kinase and mTOR/p70s6k inhibitors ... Cardiac ventricular tissue were homogenized in lysis buffer and tissue debris were removed by centrifugation at 3000 rpm (10 ...
... studies using the mTORC1-specific inhibitor rapamycin have revealed a broader role of mTORC1 in regulating the metabolic ... function for mTORC1 is the promotion of protein synthesis through the phosphorylation of at least two direct downstream targets ... Cellular energy depletion results in the activation of AMP-activated protein kinase (AMPK) by the tumor suppressor protein LKB1 ... However, pre-trial studies show that 2-DG, as is the case with other glycolysis inhibitors, does not have a significant effect ...
... mTOR regulates protein synthesis via multiple phosphorylation targets, including p70S6 kinase, a regulator of ribosome function ... The lack of specific inhibitors for Akt has made it difficult to go beyond correlating Akt activity with lymphocyte glucose ... mammalian target of rapamycin; AMPK, AMP-dependent protein kinase. ... However, most studies of the control mechanisms have used the metabolically specialized tissues of liver, muscle, and ...
  • By contrast, most differentiated cells primarily metabolize glucose to carbon dioxide by oxidation of pyruvate in the mitochondrial tricarboxylic acid (TCA) cycle, a process known as oxidative phosphorylation that requires far less glucose to generate the same amount of energy. (biomedcentral.com)
  • Conversely, it is involved in non-gene mechanisms as well, such as regulation of key enzymes for lipid and protein metabolism and blood glucose homeostasis [ 7 ]. (hindawi.com)
  • Evidence in support of such adaptations was obtained nearly a century ago by Otto Warburg, and Carl and Gert Cori and their colleagues when they demonstrated an increased uptake of glucose by tumors as compared to normal tissues [ 1 , 2 ]. (mdpi.com)
  • These Atg proteins form distinct functional complexes that regulate each step of the process, including induction of autophagy, generation of the nucleation complex, autophagosome formation, and cargo recognition ( 1 ). (diabetesjournals.org)
  • In Drosophila, a key effector of Ds and Ft is the atypical myosin Dachs , which becomes planar polarised along the proximal-distal axis in developing epithelia to regulate tissue size via the Hippo pathway and tissue shape via modulating tension at junctions. (sdbonline.org)
  • In contrast, the ability of PIs to regulate protein metabolism has not been as thoroughly investigated, although there is evidence that HIV-related wasting still occurs in patients treated with these drugs ( 32 ). (physiology.org)
  • These phosphorylation events act as molecular on/off switches that can modulate or regulate the target protein biological function. (allindianpatents.com)
  • In the nucleus, the Smad complexes bind to other DNA-binding transcription factors, co-activators, and co-repressors to regulate the expression of a wide variety of target genes. (biomedcentral.com)
  • The data here show that autophagy in Saccharomyces cerevisiae is also controlled by the cAMP-dependent protein kinase (PKA) pathway. (pnas.org)
  • Macroautophagy (hereafter autophagy) is a highly-conserved membrane trafficking pathway that is responsible for the turnover of bulk cytoplasmic protein and organelles ( 1 , 2 ). (pnas.org)
  • However, recent studies indicate that autophagy is involved in a wide variety of physiological processes, including tissue remodeling during development, the removal of protein aggregates, and innate immune responses ( 5 , 6 ). (pnas.org)
  • The cellular components mediating autophagy were initially described in S. cerevisiae , and orthologs of many of these Atg proteins have since been identified in other eukaryotes ( 10 , 11 ). (pnas.org)
  • The second form of autophagy, chaperone-mediated autophagy, displays functional selectivity for the lysosomal targeting of specific soluble cytosolic proteins with the KFERQ signature ( 7 ) and requires the lysosome-associated membrane protein-2A receptor ( 7 ). (diabetesjournals.org)
  • conversely, autophagy inhibitors stabilize SQSTM1 levels. (cellsignal.com)
  • They also include the action of proinflammatory cytokines, the production of reactive oxygen species, DNA fragmentation (typical of necroptosis in type 1 diabetic patients), excessive production of islet amyloid polypeptide with the consequent endoplasmic reticulum stress, disruption in autophagy mechanisms, and protein complex formation, such as the inflammasome, capable of increasing oxidative stress produced by mitochondrial damage. (hindawi.com)
  • Whilst the overall effects of mTORC1 signalling differ in cells and tissues, it has an evolutionarily conserved role in promoting anabolic cell growth and inhibiting the catabolic process of autophagy. (embopress.org)
  • To gain insight into possible modes of collateral sensitivity, we performed in silico molecular docking studies of honokiol to EGFR and EGFR-related downstream signal proteins. (thefreelibrary.com)
  • The molecular identification of genes encoding enzymes that catalyze steps in TAG biosynthesis from glycerol 3-phosphate has revealed an unexpected number of protein isoforms of the glycerol phosphate acyltransferase (GPAT), acylglycerolphosphate acyltransferase (AGPAT), and lipin (phosphatidate phosphatase) families that appear to catalyze similar biochemical reactions. (physiology.org)
  • Studies to date have made it abundantly clear that HDACi treatment results in a plethora of molecular changes, which are not always linked to histone acetylation, and that there is an essential need to understand the specific target(s) of any HDACi of interest. (biomedsearch.com)
  • Given that CSF-1R inhibitors are currently in clinical trials for multiple cancer types including for GBM, understanding the molecular mechanisms that underlie non-responsive/ resistant tumors is timely and critical. (omicsdi.org)
  • The observed clinical efficacy of mTOR inhibitors in patients with RCC may be mediated in part by the dependence of efficient hypoxia-inducible factor translation on the mTOR pathway. (aacrjournals.org)
  • Cyclins are a family of proteins characterised by a homology region, containing approximately 100 amino acids, termed the "cyclin box" which is used in binding to, and defining selectivity for, specific CDK partner proteins. (allindianpatents.com)