Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We previously have demonstrated that intramolecular interactions between alpha beta-alpha beta subunits are necessary for insulin-dependent activation of the protein kinase domain within a single alpha 2 beta 2 heterotetrameric insulin-receptor complex (Wilden, P. A., Morrison, B. D., and Pessin, J. E. (1989) Biochemistry 28, 785-792). To evaluate the role of the beta subunit transmembrane domain in the insulin-dependent signalling mechanism, mutant human insulin receptors containing a series of nested transmembrane domain deletions (amino acids 941-945) were generated and stable Chinese hamster ovary-transfected cell lines were obtained. In addition, a substitution of Val-938 for Glu (E/V938) similar to the oncogenic mutation found in the neu transmembrane domain was also introduced into the insulin receptor. Scatchard analysis of insulin binding to the stable Chinese hamster ovary cell lines expressing either wild type or mutant insulin receptors indicated equivalent receptor number (2-4 x 10(6)/cell) and similar high affinity binding constants (Kd 0.1-0.3 nM). 125I-Insulin affinity cross-linking demonstrated that all of the expressed insulin receptors were assembled and processed into alpha 2 beta 2 heterotetrameric complexes. Surprisingly, all the mutant insulin receptors retained insulin-stimulated autophosphorylation both in vivo and in vitro. Furthermore, endogenous substrate phosphorylation in vivo as well as insulin-stimulated thymidine incorporation into DNA were unaffected by the transmembrane domain mutations. These data demonstrate that marked structural alterations in the insulin receptor transmembrane domain do not interfere with insulin-dependent signal transduction.
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PMID:Evidence supporting a passive role for the insulin receptor transmembrane domain in insulin-dependent signal transduction. 203 70

The alpha beta heterodimeric form of untreated hepatic insulin receptor was a substrate for casein kinase 2, whereas the alpha 2 beta 2 heterotetramer was not. On the contrary, autophosphorylation was detected only in the heterotetramer. Dissociation of the receptor by treatment with dithiothreitol decreased its autophosphorylation but favoured phosphorylation of its beta-subunit by casein kinase 2.
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PMID:Dissociation of the hepatic insulin receptor favours its phosphorylation by casein kinase 2. 203 67

The insulin receptor is an integral part of plasma membrane of most cells. It consists of 2 alpha and two beta subunits. The alpha subunit is the hormone binding component, while beta subunits are a tyrosine specific protein kinase which itself can be autophosphorylated. Receptor tyrosine kinase activation upon insulin binding catalyses the phosphorylation of exogenous substrates and endogenous cellular proteins. It is reasonable to think that the insulin induced autophosphorylation, activation of its receptor kinase and changes in intracellular substrates represent important events in the action of insulin on cell metabolism and growth.
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PMID:[The structure and mechanism of action of insulin receptors]. 209 92

The mature product of the c-met proto-oncogene is a putative tyrosine kinase receptor of 190 kd with an alpha beta heterodimeric structure. The c-met protein is phosphorylated in vivo on the beta subunit in the gastric carcinoma cell line GTL-16 (Giordano et al., 1988). Western blots with phosphotyrosine antibodies show that tyrosine phosphorylation of the beta subunit is reduced by treatment of GTL-16 cells with protein kinase C activators (tumor promoting phorbol esters such as phorbol 12-myristate 13-acetate, TPA, and beta-phorbol 12,13-dibutyrate, PdBu, or membrane permeable synthetic diacylglycerol 1-oleyl-2-acetyl-sn-glycerol, OAG). The inactive analog alpha-phorbol 12,13-didecanoate has no effect. The inhibition induced by TPA is dose dependent and maximal after 1 h. Depletion of protein kinase-C by prolonged treatment with TPA (18-48 h) increases the phosphorylation on tyrosine of the beta subunit. Phospho-amino acid analysis of the c-met protein immunoprecipitated from [32P]orthophosphate-labelled GTL-16 cells shows that protein kinase-C activation leads to an increase in serine phosphorylation and to concomitant decrease in tyrosine phosphorylation. These results suggest that, similar to the EGF and insulin receptor, the putative receptor encoded by the c-met proto-oncogene may be negatively modulated by protein kinase-C phosphorylation.
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PMID:Protein kinase-c activation inhibits tyrosine phosphorylation of the c-met protein. 211 5

Increased hepatic glucose production is responsible for fasting hyperglycemia in type II diabetes. Insulin resistance is the key in this process because of the inability of insulin to suppress hepatic glucose production, thereby allowing an unopposed glucagon effect. Glyburide, one of the second-generation sulfonylureas, decreases glucose production and enhances insulin action in the liver. Available data suggest that glyburide: (1) enhances glycogen synthesis in the liver by increasing glycogen synthase; (2) inhibits glycogenolysis by decreasing phosphorylase alpha activity; and (3) decreases gluconeogenesis and stimulates glycolysis by decreasing A-kinase activity, which results in increased fructose 2,6-bisphosphate, one of the key regulators of carbohydrate metabolism in the liver. The effect of glyburide on the insulin-signaling mechanism(s) is distal to the insulin binding site of the alpha-subunit of the insulin receptor and the tyrosine kinase activation site of the beta-subunit.
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PMID:Effects of glyburide on carbohydrate metabolism and insulin action in the liver. 211 86

In these studies we demonstrate that insulin stimulates both tyrosine and serine phosphorylation of the insulin receptor after its partial purification on wheat germ-agarose, and after affinity purification on insulin-agarose. Analysis of the serine phosphate incorporated into partially purified or highly purified insulin receptor suggests that an insulin-sensitive serine kinase (IRSK) copurifies with the insulin receptor. Following trypsin digestion, reversed-phase high pressure liquid chromatography (HPLC) analysis of the phosphorylated, affinity-purified insulin receptor preparation reveals phosphopeptide profiles similar to those of trypsin-digested receptors immunoprecipitated from 32P-labeled fibroblasts overexpressing the human insulin receptor. The major insulin-stimulated HPLC phosphopeptide peak from insulin receptors labeled in intact cells contains a hydrophilic phosphoserine-containing peptide which rapidly elutes from a C18 column. HPLC and two-dimensional separation indicate that the same phosphopeptide is obtained when affinity-purified insulin receptors are phosphorylated by IRSK. The serine containing tryptic peptide within the cytoplasmic domain of the human insulin receptor predicted to elute most rapidly upon HPLC had the sequence SSHCQR corresponding to residues 1293-1298. A synthetic peptide containing this sequence is phosphorylated by the insulin receptor/IRSK preparation. After alkylation and trypsin digestion, the synthetic phosphopeptide comigrates with the alkylated, tryptic phosphopeptide derived from insulin receptor phosphorylated in vitro by IRSK. We propose that serine 1293 or 1294 of the human insulin receptor is a major site(s) phosphorylated on the insulin receptor in intact cells and is phosphorylated by IRSK. Furthermore, insulin added directly to affinity-purified insulin receptor/IRSK preparations stimulates the phosphorylation of synthetic peptides corresponding to this receptor phosphorylation site and another containing threonine 1336. Kemptide phosphorylation is not stimulated by insulin under these conditions. No phosphorylation of peptide substrates for Ca2+/calmodulin-dependent protein kinase, protein kinase C, casein kinase II, or cGMP-dependent protein kinase by IRSK is detected. These data indicate that IRSK exhibits specificity for the insulin receptor and may be activated by the insulin receptor tyrosine kinase in an insulin-dependent manner.
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PMID:Insulin-sensitive phosphorylation of serine 1293/1294 on the human insulin receptor by a tightly associated serine kinase. 213 51

The abilities of a series of six mutants of the human insulin receptor, an insulin receptor/v-ros hybrid (IR-ros) and the P68gag-ros transforming protein to stimulate S6 protein kinase have been assessed. Insulin receptor mutants in which either 1 or 2 tyrosine residues have been replaced with phenylalanine (YF1, YF3) have lost some or all of the capacity to mediate the activation of S6 kinase in response to insulin. None of the four mutants that contain deletions (spBam, spBamYF3, iBgl, T-t) elicit an insulin-dependent stimulation of S6 kinase. A previous study of the IRros hybrid receptor demonstrated that it was unable to cause either insulin-stimulated thymidine incorporation or glucose uptake (Ellis, L., Morgan, D. O., Jong, S.-M., Wang, L.-H., Roth, R. A., and Rutter, W. J. (1987) Proc. Natl. Acad. Sci. U. S. A. 84, 5101-5105). In contrast, the IRros chimera appears to mediate the activation of S6 protein kinase by insulin. In further evaluating the biological activities of the IRros hybrid, we have examined its effects on a microtubule-associated protein-2 (MAP2) kinase that is thought to be an early target in the cascade of reactions leading to increased S6 phosphorylation (Sturgill, T. W., Ray, L. B., Erickson, E., and Maller, J. L. (1988) Nature 334, 715-718). We find that the IRros receptor stimulates the MAP2 protein kinase from 3- to 6-fold in insulin-treated cells, conferring more than a 30-fold increase in the insulin sensitivity of MAP2 kinase activation.
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PMID:Evidence for insulin-dependent activation of S6 and microtubule-associated protein-2 kinases via a human insulin receptor/v-ros hybrid. 215 57

The enhanced phosphorylations via cAMP, Ca2+ mobilization, and diacyl glycerol formation via the activation of the respective kinases is now classical. The decreased phosphorylation via inhibition of adenylate cyclase via the alpha adrenergic receptor is also becoming understood. What the insulin studies on the control of glycogen synthesis have taught us is that the rate limiting enzyme glycogen synthase is regulated by multiple covalent phosphorylation in an elegant but complex manner. The overall pattern of dephosphorylation is influenced by effecting both phosphatase and kinase activities in a set of interrelated mechanisms. In the presence of glucose, in muscle, fat, and liver under physiological conditions G-6-P acts as a signal to stimulate the phosphatase. An additional stimulation could occur via a novel insulin phosphatase stimulatory mediator. The phosphatase is also stimulated by at least three covalent mechanisms involving altered phosphorylation state. In one there is a decreased phosphorylation of the phosphatase inhibitor 1 potentially related to decreased cAMP-dependent protein kinase activity. In the second, there is decreased phosphorylation of the deinhibitor also potentially related to decreased cAMP-dependent protein kinase phosphorylation. In the third, an increased activity of casein kinase 2 could activate the ATP-Mg dependent phosphatase by an increased phosphorylation of phosphatase inhibitor 2 (modulatory subunit). In the liver, allosteric control of the phosphatase by G-6-P and nucleotides is of great importance. Insulin also stimulates the phosphatase in long-term experiments via increased protein synthesis. It is clear that future work will be required to determine which species of the various classes of phosphatases are regulated in short-term and long-term regulation by insulin. In terms of kinases, the effects of insulin to inactivate and desensitize the cAMP-dependent protein kinase are established. The molecular mechanisms of this effect remain to be worked out. The enhanced activity of MAP and S-6 kinase would appear to be part of a cascade of reactions perhaps originating in the autophosphorylation and activation of the insulin receptor tyrosine kinase. The mechanism of the short-term activation of casein kinase 2 remains to be elucidated. A cAMP-dependent protein kinase inhibitory mediator, which also inhibits adenylate cyclase is an important element in the regulation of kinase and adenylate cyclase activity by insulin. Its physiological significance must be established in the future, in terms of its control of glycogen synthase activation by insulin. Clearly this kinase inhibitor as well as the phosphatase stimulator are potential regulators of glycogen synthase activity by insulin.
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PMID:Insulin and the stimulation of glycogen synthesis. The road from glycogen structure to glycogen synthase to cyclic AMP-dependent protein kinase to insulin mediators. 215 10

Several studies suggest that the tyrosine-specific protein kinase activity of the beta-subunit of the insulin receptor is necessary to mediate the biological effects of insulin. This conclusion leads to the hypothesis that the effect of insulin is mediated through the tyrosine phosphorylation of cellular substrates by the insulin-receptor tyrosine kinase. In this review, the experimental evidence regarding insulin-stimulated phosphorylation of proteins both in vitro and in vivo is evaluated. In a cell-free system, tubulin, microtubule-associated protein 2, tau, fodrin, calmodulin-dependent kinase, calmodulin, and lipocortins 1 and 2 were reported to be good substrates for insulin-receptor kinase. However, none were found to be tyrosine phosphorylated in an intact-cell system. In intact-cell systems, proteins of Mr 185,000 (pp185), 120,000 (pp120), 240,000 (pp240), 15,000 (pp15), 60,000 (pp60), and 62,000 (pp62) as well as several others were reported to be tyrosine phosphorylated in an insulin-dependent fashion. However, the function or functional alteration of these proteins induced by insulin-stimulated tyrosine phosphorylation is not clear. Therefore, physiologically relevant substrates for the insulin-receptor kinase have not been established, and more work is necessary to verify the phosphorylation cascade hypothesis of insulin action.
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PMID:Substrates for insulin-receptor kinase. 215 95

The control of cell proliferation involves both regulatory events initiated at the plasma membrane that control reentry into the cell cycle and intracellular biochemical changes that direct the process of cell division itself. Both of these aspects of cell growth control can be studied in Xenopus oocytes undergoing meiotic maturation in response to mitogenic stimulation. All mitogenic signaling pathways so far identified lead to the phosphorylation of ribosomal protein S6 on serine residues, and the biochemistry of this event has been investigated. Insulin and other mitogens activate ribosomal protein S6 kinase II, which has been cloned and sequences in oocytes and other cells. This enzyme is activated by phosphorylation on serine and threonine residues by an insulin-stimulated protein kinase known as MAP-2 kinase. MAP kinase itself is also activated by direct phosphorylation on threonine and tyrosine residues in vivo. These results reconstitute one step of the insulin signaling pathway evident shortly after insulin receptor binding at the membrane. Several hours after mitogenic stimulation, a cell cycle cytoplasmic control element is activated that is sufficient to cause entry into M phase. This control element, known as maturation-promoting factor or MPF, has been purified to near homogeneity and shown to consist of a complex between p34cdc2 protein kinase and cyclin B2. In addition to apparent phosphorylation of cyclin, regulation of MPF activity involves synthesis of the cyclin subunit and its periodic degradation at the metaphase----anaphase transition. The p34cdc2 kinase subunit is regulated by phosphorylation/dephosphorylation on threonine and tyrosine residues, being inactive when phosphorylated and active when dephosphorylated. Analysis of phosphorylation sides in histone H1 for p34cdc2 has revealed a consensus sequence of (K/R)S/TP(X)K/R, where the elements in parentheses are present in some but not all sites. Sites with such a consensus are specifically phosphorylated in mitosis and by MPF in the protooncogene pp60c-src. These results provide a link between cell cycle control and cell growth control and suggest that changes in cell adhesion and the cytoskeleton in mitosis may be regulated indirectly by MPF via protooncogene activation. S6 kinase II is also activated upon expression of MPF in cells, indicating that MPF is upstream of S6 kinase on the mitogenic signaling pathway. Further study both of the signaling events that lead to MPF activation and of the substrates for phosphorylation by MPF should lead to a comprehensive understanding of the biochemistry of cell division.
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PMID:Xenopus oocytes and the biochemistry of cell division. 215 26


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