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)

A property of signal transduction pathways that might explain their efficiency and specificity is the formation of signaling complexes. The recent demonstration that adaptor proteins can interact with many components of the extracellular signal-regulated kinases (ERKs) signaling cascade leads us to investigate whether such complexes may include the transmembrane receptor. The present work shows that in human hepatoma Hep3B cells, insulin receptor (IR) can be coimmunoprecipitated with other components of the ERKs cascade: insulin receptor substrate (IRS), Raf-1, and ERKs. Furthermore, these complexes formed near the cytoplasmic membrane even prior to insulin stimulation.
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PMID:Complexes formation between insulin receptor and extracellular signal-regulated kinases ERKs. 1140 18

We determined the involvement of Tyr-1158 within the regulatory loop of the insulin receptor (IR) in the generation of insulin-specific responses in situ. For this purpose chimeric receptors with an epidermal growth factor (EGF) receptor extracellular domain and an IR cytoplasmic domain (EIR) were constructed, which allow activation of the cytoplasmic IR domain without activation of endogenous wt-IRs. Tyr-1158 of the chimera EIR was exchanged for Phe, creating a mutant chimeric receptor (EIR-Y1158F). Chimeric receptors were expressed in 3T3-L1 pre-adipocytes, which do not show insulin-specific responses upon EGF stimulation. We found that pre-adipocytes expressing EIR-Y1158F were impaired in their ability to stimulate glycogen synthesis and DNA synthesis upon maximal stimulation with EGF. EIR-Y1158F was impaired in its ability to phosphorylate insulin receptor substrate (IRS)-1 and induce downstream signals of IRS-1 phosphorylation, such as the association of IRS-1 with phosphatidyl-inositol-3'-kinase and the activation of protein kinase B (Akt). In contrast with the phosphorylation of IRS-1, the phosphorylation of IRS-2 and extracellular regulated protein kinase-1/-2 was normal in EIR-Y1158F expressing cells. These observations suggest that the level of IRS-1 phosphorylation rather than the level of IRS-2 phosphorylation mediates insulin-induced glycogen synthesis and DNA synthesis in 3T3-L1 pre-adipocytes.
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PMID:IRS-1 tyrosine phosphorylation reflects insulin-induced metabolic and mitogenic responses in 3T3-L1 pre-adipocytes. 1147 Oct 71

Activation of the G-protein-coupled receptor for glucose-dependent insulinotropic polypeptide facilitates insulin-release from pancreatic beta-cells. In the present study, we examined whether glucose-dependent insulinotropic polypeptide also acts as a growth factor for the beta-cell line INS-1. Here, we show that glucose-dependent insulinotropic polypeptide induced cellular proliferation synergistically with glucose between 2.5 mM and 15 mM by pleiotropic activation of signaling pathways. Glucose-dependent insulinotropic polypeptide stimulated the signaling modules of PKA/cAMP regulatory element binder, MAPK, and PI3K/protein kinase B in a glucose- and dose-dependent manner. Janus kinase 2 and signal transducer and activators of transcription 5/6 pathways were not stimulated by glucose-dependent insulinotropic polypeptide. Activation of PI3K by glucose-dependent insulinotropic polypeptide and glucose was associated with insulin receptor substrate isoforms insulin receptor substrate-2 and growth factor bound-2 associated binder-1 and PI3K isoforms p85alpha, p110alpha, p110beta, and p110gamma. Downstream of PI3K, glucose-dependent insulinotropic polypeptide-stimulated protein kinase Balpha and protein kinase Bbeta isoforms and phosphorylated glycogen synthase kinase-3, forkhead transcription factor FKHR, and p70S6K. These data indicate that glucose-dependent insulinotropic polypeptide functions synergistically with glucose as a pleiotropic growth factor for insulin-producing beta-cells, which may play a role for metabolic adaptations of insulin-producing cells during type II diabetes.
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PMID:Glucose-dependent insulinotropic polypeptide is a growth factor for beta (INS-1) cells by pleiotropic signaling. 1151 6

The insulin signaling cascade was investigated in rat myocardium in vivo in the presence of streptozocin (STZ)-induced diabetes and after diabetes treatment by islet transplantation under the kidney capsule. The levels of insulin-stimulated tyrosine phosphorylation of the insulin receptor beta-subunit, insulin receptor substrate (IRS)-2, and p52(Shc) were increased in diabetic compared with control heart, whereas tyrosine phosphorylation of IRS-1 was unchanged. The amount of the p85 subunit of phosphatidylinositol 3-kinase (PI 3-kinase) and the level of PI 3-kinase activity associated with IRS-2 were also elevated in diabetes, whereas no changes in IRS-1-associated PI 3-kinase were observed. Insulin-induced phosphorylation of Akt on Thr-308 was increased fivefold in diabetic heart, whereas Akt phosphorylation on Ser-473 was normal. In contrast with Akt phosphorylation, insulin-induced phosphorylation of glycogen synthase kinase (GSK)-3, a major cellular substrate of Akt, was markedly reduced in diabetes. In islet-transplanted rats, the majority of the alterations in insulin-signaling proteins found in diabetic rats were normalized, but insulin stimulation of IRS-2 tyrosine phosphorylation and association with PI 3-kinase was blunted. In conclusion, in the diabetic heart, 1) IRS-1, IRS-2, and p52(Shc) are differently altered, 2) the levels of Akt phosphorylation on Ser-473 and Thr-308, respectively, are not coordinately regulated, and 3) the increased activity of proximal-signaling proteins (i.e., IRS-2 and PI 3-kinase) is not propagated distally to GSK-3. Islet transplantation under the kidney capsule is a potentially effective therapy to correct several diabetes-induced abnormalities of insulin signaling in cardiac muscle but does not restore the responsiveness of all signaling reactions to insulin.
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PMID:Effects of streptozocin diabetes and diabetes treatment by islet transplantation on in vivo insulin signaling in rat heart. 1172 53

Genetic studies in Drosophila melanogaster underscore the importance of the insulin-signalling pathway in controlling cell, organ and animal size. Effectors of this pathway include Chico (the insulin receptor substrate homologue), dPI(3)K, dPKB, dPTEN, and dS6K. Mutations in any of these components have a striking effect on cell size and number, with the exception of dS6K. Mutants in dS6K affect cell size but not cell number, seemingly consistent with arguments that dS6K is a distal effector in the signalling pathway, directly controlled by dTOR, a downstream effector of dPI(3)K and dPKB. Unexpectedly, recent studies showed that dS6K activity is unimpaired in chico-deficient larvae, suggesting that dS6K activation may be mediated through the dPI(3)K docking sites of the Drosophila insulin receptor. Here, we show genetically, pharmacologically and biochemically that dS6K resides on an insulin signalling pathway distinct from that of dPKB, and surprisingly also from that of dPI(3)K. More striking, despite dPKB-dPI(3)K-independence, dS6K activity is dependent on the Drosophila homologue of the phosphoinositide-dependent protein kinase 1, dPDK1, demonstrating that both dPDK1, as well as dTOR, mediated dS6K activation is phosphatidylinositide-3,4,5-trisphosphate (PIP3)-independent.
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PMID:dS6K-regulated cell growth is dPKB/dPI(3)K-independent, but requires dPDK1. 1186 17

Transforming growth factor (TGF)-alpha- and epidermal growth factor (EGF)-induced signal transduction was directly compared with that of glucose and insulin-like growth factor-1 (IGF-1) in INS-1 cells. TGF-alpha/EGF transiently (<20 min) induced phosphorylation of extracellular-regulated kinase (Erk)-1/2 (>20-fold), glycogen synthase kinase (GSK)-3 (>10-fold), and protein kinase B (PKB) (Ser(473) and Thr(308)), but did not increase [(3)H]thymidine incorporation. In contrast, phosphorylation of Erk1/2, GSK-3, and PKB in response to glucose and IGF-1 was more prolonged (>24 h) and, though not as robust as TGF-alpha/EGF, did increase beta-cell proliferation. Phosphorylation of p70(S6K) was also increased by IGF-1/glucose, but not by TGF-alpha/EGF, despite upstream PKB activation. It was found that IGF-1 induced phosphatidylinositol 3-kinase (PI3K) association with insulin receptor substrate (IRS)-1 and -2 in a glucose-dependent manner, whereas TGF-alpha/EGF did not. The importance of specific IRS-2-mediated signaling events was emphasized in that adenoviral-mediated overexpression of IRS-2 further increased glucose/IGF-1-induced beta-cell proliferation (more than twofold; P < 0.05) compared with control or adenoviral-mediated IRS-1 overexpressing INS-1 cells. Neither IRS-1 nor IRS-2 overexpression induced a beta-cell proliferative response to TGF-alpha/EGF. Thus, a prolonged activation of Erk1/2 and PI3K signaling pathways is important in committing a beta-cell to a mitogenic event, and it is likely that this sustained activation is instigated by signal transduction occurring specifically through IRS-2.
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PMID:Activation of IRS-2-mediated signal transduction by IGF-1, but not TGF-alpha or EGF, augments pancreatic beta-cell proliferation. 1191 14

The thiazolidenedione, rosiglitazone, increases basal and/or insulin-stimulated glucose transport in various cell types by diverse but uncertain mechanisms that may involve insulin receptor substrate (IRS)-1-dependent PI3K. Presently, in 3T3/L1 adipocytes, rosiglitazone induced sizable increases in basal glucose transport that were: dependent on PI3K, 3-phosphoinositide-dependent protein kinase-1 (PDK-1), and PKC-lambda; accompanied by increases in tyrosine phosphorylation of Cbl and Cbl-dependent increases in PI3K and PKC-lambda activity; but not accompanied by increases in IRS-1/2-dependent PI3K or protein kinase B activity. Additionally, rosiglitazone increased IRS-1 and IRS-2 levels, thereby enhancing insulin effects on IRS-1- and IRS-2-dependent PI3K and downstream signaling factors PKC-lambda and protein kinase B. Our findings suggest that Cbl participates in mediating effects of rosiglitazone on PI3K, PDK-1, and PKC-lambda and the glucose transport system and that this Cbl-dependent pathway complements the IRS-1 and IRS-2 pathways for activating PI3K, PDK-1, and PKC-lambda during combined actions of rosiglitazone and insulin in 3T3/L1 cells.
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PMID:Cbl, IRS-1, and IRS-2 mediate effects of rosiglitazone on PI3K, PKC-lambda, and glucose transport in 3T3/L1 adipocytes. 1195 52

Sunghyangjungisan (SHJS) is a commonly prescribed drug for cerebrovascular diseases in Oriental medicine. The water extract of SHJS was found to be protective against neurotoxicity elicited by deprivation of tropic factors. SHJS inhibited the activation of caspase 3-like protease and nucleosome-sized DNA fragmentation in serum-deprived PC12 Pheochromocytoma cells. Interestingly, pretreatment with an inhibitor of protein kinase A, KT5720 inhibited the neuroprotective effects of SHJS via inhibition of capase 3-like protease activation. When PC12 cells were treated with SHJS, Ser133 phosphorylation of cAMP-responsive elements binding protein (CREB), a transcription factor, was also increased in a time- and dose-dependent manner. In addition, CRE DNA binding activity of CREB was also increased in a time-dependent manner. SHJS-induced CRE binding activity was blocked by KT5720. Taken together, we suggest the possibility that SHJS may provide a neuroprotective effects on serum-deprived apoptosis of PC12 cells in a CREB- and CRE-dependent manner.
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PMID:Sunghyangjungisan protects PC12 cells against neurotoxicity elicited by withdrawal of trophic support via CRE activation. 1202 48

Nuclear factor-kappaB (NF-kappaB) prevents hepatocytes from undergoing apoptosis during development and liver regeneration. Mice with inactivated glycogen synthase kinase (GSK)-3beta die from hepatocyte apoptosis during development due to a defect in NF-kappaB activation (Hoeflich KP, Luo J, Rubie EA, Tsao MS, Jin O, and Woodgett JR. Nature 406: 86-90, 2000). In this study, we determined the role of GSK-3 in TNF-alpha-induced NF-kappaB activation and cell death in primary hepatocytes. LiCl, an established inhibitor of GSK-3, sensitized primary rat hepatocytes toward TNF-alpha-mediated apoptosis resulting in 90% cell death after 24 h. This was accompanied by increased caspase 8-like and 3-like activities, nuclear fragmentation and DNA laddering. LiCl treatment had no effect on IkappaB-alpha degradation, IkappaB kinase (IKK) activity, NF-kappaB binding activity, and p65 nuclear import and export, but decreased transcription of the NF-kappaB-dependent inducible nitric oxide synthase gene and a NF-kappaB-driven reporter gene. The p65 sequence revealed four potential GSK-3 phosphorylation sites within its COOH-terminal transactivation domains and recombinant GSK-3beta phosphorylated glutathione S-transferase (GST)-p65(354-551), but not GST-p65(1-305) in vitro. These results indicate that GSK-3 protects hepatocytes from TNF-alpha-induced apoptosis through p65 phosphorylation and upregulation of NF-kappaB transactivation.
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PMID:Role of glycogen synthase kinase-3 in TNF-alpha-induced NF-kappaB activation and apoptosis in hepatocytes. 1206 8

Brassinosteroids (BRs) are a class of steroid hormones essential for normal growth and development in plants. BR signaling involves the cell-surface receptor BRI1, the glycogen synthase kinase-3-like kinase BIN2 as a negative regulator, and nuclear proteins BZR1 and BZR2/BES1 as positive regulators. The interactions among these components remain unclear. Here we report that BRs induce dephosphorylation and accumulation of BZR1 protein. Experiments using a proteasome inhibitor, MG132, suggest that phosphorylation of BZR1 increases its degradation by the proteasome machinery. BIN2 directly interacts with BZR1 in yeast two-hybrid assays, phosphorylates BZR1 in vitro, and negatively regulates BZR1 protein accumulation in vivo. These results strongly suggest that BIN2 phosphorylates BZR1 and targets it for degradation and that BR signaling causes BZR1 dephosphorylation and accumulation by inhibiting BIN2 activity.
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PMID:The GSK3-like kinase BIN2 phosphorylates and destabilizes BZR1, a positive regulator of the brassinosteroid signaling pathway in Arabidopsis. 1211 46


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