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)

Insulin receptor substrate-1 (IRS-1), a substrate of various receptor tyrosine kinases transmits mitogenic signals initiated by extracellular ligands. This protein is involved in normal hepatocyte growth and has been found to be overexpressed in human hepatocellular carcinoma. Expression of a carboxy-terminal truncated IRS-1 molecule containing the pleckstrin homology and phosphotyrosine-binding domains associates with the insulin receptor and prevents tyrosyl phosphorylation of endogenous IRS-1 and Shc proteins. Thus, subsequent activation of downstream signaling molecules induced by insulin and IGF-1 such as phosphatidylinositol-3 kinase and mitogen activated protein kinase is inhibited. The morphologic features of transformed human hepatocellular carcinoma cells change to a differentiated hepatocyte appearance and characteristics of the malignant phenotype as manifested by anchorage independent cell growth and tumor formation in nude mice are lost. These studies demonstrate that signal transduction pathways mediated through or by IRS-1 are important in hepatocyte and human hepatocellular carcinoma cell growth.
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PMID:A carboxy-terminal truncated insulin receptor substrate-1 dominant negative protein reverses the human hepatocellular carcinoma malignant phenotype. 890 30

Insulin receptor substrate (IRS) proteins play a crucial role as signaling molecules in insulin action. Serine phosphorylation of IRS proteins has been hypothesized as a cause of attenuating insulin signaling. The current study investigated serine kinase activity toward IRS-1 in several models of insulin resistance. An in vitro kinase assay was developed that used partially purified cell lysates as a kinase and glutathione S-transferase fusion proteins that contained various of IRS-1 fragments as substrates. Elevated serine kinase activity was detected in Chinese hamster ovary/insulin receptor (IR)/IRS-1 cells and 3T3-L1 adipocytes chronically treated with insulin, and in liver and muscle of obese JCR:LA-cp rats. It phosphorylated the 526-859 amino acid region of IRS-1, whereas phosphorylation of the 2-516 and 900-1235 amino acid regions was not altered. Phosphopeptide mapping of the 526-859 region of IRS-1 showed three major phosphopeptides (P1, P2, and P3) with different patterns of phosphorylation depending on the source of serine kinase activity. P1 and P2 were strongly phosphorylated when the kinase activity was prepared from insulin-resistant Chinese hamster ovary/IR/IRS-1 cells, weakly phosphorylated by the kinase activity from insulin-resistant 3T3-L1 adipocytes, and barely phosphorylated when the extract was derived from insulin-resistant liver. In contrast, P3 was phosphorylated by the serine kinase activity prepared from all insulin-resistant cells and tissues of animals. P1 and P2 phosphorylation can be explained by mitogen-activated protein kinase activity based on the phosphopeptide map generated by recombinant ERK2. In contrast, mitogen-activated protein kinase failed to phosphorylate the P3 peptide, suggesting that another serine kinase regulates this modification of IRS-1 in insulin-resistant state.
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PMID:Identification of enhanced serine kinase activity in insulin resistance. 1018 59

Insulin resistance is a key pathophysiologic feature of obesity and type 2 diabetes and is associated with other human diseases, including atherosclerosis, hypertension, hyperlipidemia, and polycystic ovarian disease. Yet, the specific cellular defects that cause insulin resistance are not precisely known. Insulin receptor substrate (IRS) proteins are important signaling molecules that mediate insulin action in insulin-sensitive cells. Recently, serine phosphorylation of IRS proteins has been implicated in attenuating insulin signaling and is thought to be a potential mechanism for insulin resistance. However, in vivo increased serine phosphorylation of IRS proteins in insulin-resistant animal models has not been reported before. In the present study, we have confirmed previous findings in both JCR:LA-cp and Zucker fatty rats, two genetically unrelated insulin-resistant rodent models, that an enhanced serine kinase activity in liver is associated with insulin resistance. The enhanced serine kinase specifically phosphorylates the conserved Ser(789) residue in IRS-1, which is in a sequence motif separate from the ones for MAPK, c-Jun N-terminal kinase, glycogen-synthase kinase 3 (GSK-3), Akt, phosphatidylinositol 3'-kinase, or casein kinase. It is similar to the phosphorylation motif for AMP-activated protein kinase, but the serine kinase in the insulin-resistant animals was shown not to be an AMP-activated protein kinase, suggesting a potential novel serine kinase. Using a specific antibody against Ser(P)(789) peptide of IRS-1, we then demonstrated for the first time a striking increase of Ser(789)-phosphorylated IRS-1 in livers of insulin-resistant rodent models, indicating enhanced serine kinase activity in vivo. Taken together, these data strongly suggest that unknown serine kinase activity and Ser(789) phosphorylation of IRS-1 may play an important role in attenuating insulin signaling in insulin-resistant animal models.
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PMID:In vivo phosphorylation of insulin receptor substrate 1 at serine 789 by a novel serine kinase in insulin-resistant rodents. 1200 86

The expression of glucose-6-phosphatase (G6Pase) mRNA is repressed by insulin and stimulated by cAMP and dexamethasone, with the insulin effect dominant. Both lipids and glucose increase the expression of G6Pase mRNA under conditions in which insulin is either absent or at basal levels. The aim of the present study was to investigate dietary nutrient regulation of G6Pase mRNA and protein under postprandial conditions. Male rats (n = 6-8/group) were deprived of food for 48 h and then either remained food deprived (FD) or were refed diets containing 68% cornstarch and 12% corn oil (ST; % energy), 68% sucrose and 12% corn oil (SU) or 35% cornstarch and 45% corn oil (HF) for 3 h. Rats were anesthetized, blood was drawn from the portal vein, and the liver was removed and immediately processed for subsequent analyses. Energy intake over the 3-h refeeding period did not differ among groups (209 +/- 25 kJ). Portal vein glucose and insulin were 5.0 +/- 0.2 mmol/L and 90 +/- 18 pmol/L, respectively, in FD rats and were not significantly different among the refed groups (14.5 +/- 1.2 mmol/L and 1302 +/- 154 pmol/L, respectively). Compared with the FD rats, G6Pase mRNA was approximately 50% lower in ST and HF groups, whereas it was approximately 1.6 fold higher in SU-refed rats (P < 0.05). G6Pase activity in whole liver homogenates was lower in ST and HF rats than in FD and SU rats. Insulin receptor substrate (IRS) phosphorylation, IRS-association with phosphatidylinositol 3 (PI3)-kinase and activation of protein kinase B (PKB) were not significantly different among the refed groups. However, glycogen synthase kinase-3alpha phosphorylation was lower and cAMP response element binding protein (CREB) phosphorylation was higher in SU rats than in ST and HF refed groups. Thus, the postprandial environment after ingestion of sucrose appears to overcome the dominant effects of insulin on G6Pase mRNA, perhaps via cellular changes that reduce phosphorylation of, and therefore activate, glycogen synthase kinase-3alpha.
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PMID:Glucose-6-phosphatase activity is not suppressed but the mRNA level is increased by a sucrose-enriched meal in rats. 1251 63

Restriction of protein calories during stages of immaturity has a major influence on glucose metabolism and increases the risk of type 2 diabetes in adulthood. However, it is known that reduction of food intake alleviates insulin resistance. We previously demonstrated an improved insulin-induced glucose uptake in skeletal muscle of chronically undernourished adult rats. The purpose of this work was to investigate whether this condition is present during suckling, a period characterized by physiological insulin resistance as well as elucidate some of the underlying mechanisms. With this aim, 10-d-old pups from food-restricted dams were studied. We showed that undernourished suckling rats are glucose normotolerants, despite their depressed insulin secretion capacity. The content of the main glucose transporters in muscle, GLUT-4 and GLUT-1, was not affected by undernutrition, but fractionation studies showed an improved insulin-stimulated GLUT-4 translocation. p38MAPK protein, implicated in up-regulation of intrinsic activity of translocated GLUT-4, was increased. These changes suggest an improved insulin-induced glucose uptake associated with undernutrition. Insulin receptor content as well as that of both regulatory and catalytic phosphoinositol 3-kinase subunits was increased by food restriction. Insulin receptor substrate-1-associated phosphoinositol 3-kinase activity after insulin was enhanced in undernourished rats, as was phospho-glycogen synthase kinase-3, in line with insulin hypersensitivity. Surprisingly, protein tyrosine phosphatase-1B association with insulin receptor was also increased by undernutrition. These adaptations to a condition of severely limited nutritional resources might result in changes in the development of key tissues and be detrimental later in life, when a correct amount of nutrients is available, as the thrifty phenotype hypothesis predicts.
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PMID:Maternal food restriction enhances insulin-induced GLUT-4 translocation and insulin signaling pathway in skeletal muscle from suckling rats. 1590 22

Insulin resistance in polycystic ovary syndrome (PCOS) results from a postbinding defect in signaling. Insulin receptor and insulin receptor substrate (IRS)-1 serine hyperphosphorylation by an unidentified kinase(s) contributes to this defect. We investigated whether insulin resistance is selective, affecting metabolic but not mitogenic pathways, in skeletal muscle as it is in cultured skin fibroblasts in PCOS. Extracellular signal-regulated kinase (ERK)1/2 activation was increased in skeletal muscle tissue and in cultured myotubes basally and in response to insulin in women with PCOS compared with control women. Mitogen-activated/extracellular signal-regulated kinase kinase (MEK)1/2 was also activated in PCOS, whereas p38 mitogen-activated protein kinase phosphorylation and signaling from the insulin receptor to Grb2 was similar in both groups. The activity of p21Ras was decreased and Raf-1 abundance increased in PCOS, suggesting that altered mitogenic signaling began at this level. MEK1/2 inhibition reduced IRS-1 Ser312 phosphorylation and increased IRS-1 association with the p85 subunit of phosphatidylinositol 3-kinase in both groups. We conclude that in PCOS skeletal muscle, 1) mitogenic signaling is enhanced in vivo and in culture, 2) ERK1/2 activation inhibits association of IRS-1 with p85 via IRS-1 Ser312 phosphorylation, and 3) ERK1/2 activation may play a role in normal feedback of insulin signaling and contribute to resistance to insulin's metabolic actions in PCOS.
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PMID:Enhanced mitogenic signaling in skeletal muscle of women with polycystic ovary syndrome. 1650 39

In this study, we evaluated the activation of various insulin signaling molecules in human fat in vivo and compared signaling reactions in visceral and subcutaneous fat depots. Paired abdominal omental and subcutaneous fat biopsies were obtained from nonobese subjects with normal insulin sensitivity under basal conditions and 6 and 30 min following administration of intravenous insulin. Insulin receptor phosphorylation was more intense and rapid and insulin receptor protein content was greater in omental than in subcutaneous adipose tissue (P < 0.05). Insulin-induced phosphorylation of Akt also occurred to a greater extent and earlier in omental than in subcutaneous fat (P < 0.05) in the absence of significant changes in Akt protein content. Accordingly, phosphorylation of the Akt substrate glycogen synthase kinase-3 was more responsive to insulin stimulation in omental fat. Protein content of extracellular signal-regulated kinase (ERK)-1/2 was threefold higher in omental than in subcutaneous fat (P < 0.05), and ERK phosphorylation showed an early 6-min peak in omental fat, in contrast with a more gradual increase observed in subcutaneous fat. In conclusion, the adipocyte insulin signaling system of omental fat shows greater and earlier responses to insulin than that of subcutaneous fat. These findings may contribute to explain the biological diversity of the two fat depots.
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PMID:Insulin signaling in human visceral and subcutaneous adipose tissue in vivo. 1656 16

Mouse embryonic stem (mES) cells are pluripotent cells that can be propagated in vitro with leukemia inhibitory factor (LIF) and serum. Intracellular signaling by LIF is principally mediated by activation of STAT-3, although additional pathways for self-renewal have been described. Here, we identified a novel role for Insulin receptor substrate-1 (IRS-1) as a critical factor in mES cells self-renewal and differentiation. IRS-1 is expressed and tyrosyl phosphorylated during mES cells self-renewal. Differentiation of mES cells, by LIF withdrawal, is associated with a marked reduction in IRS-1 expression. Targeting of IRS-1 by si-IRS-1 results in a severe reduction of Oct-4 protein expression and alkaline phosphatase activity, markers of undifferentiated mES cells. IRS-1 targeting does not interfere with LIF-induced STAT-3 phosphorylation, but negatively affects protein kinase B (PKB/AKT) and glycogen synthase kinase-3 (GSK-3beta) phosphorylation, which are downstream effectors of the LIF-mediated PI3K signaling cascade. Targeting of IRS-1 also results in a marked down regulation of Id-1 and Id-2 proteins expression, which are important components for self-renewal of ES cells. Conversely, over expression of IRS-1 inhibits mES cell differentiation. Taken together, these results suggest that expression and activity of IRS-1 are critical to the maintenance of the self-renewal program in mES cells.
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PMID:Insulin receptor substrate (IRS)-1 regulates murine embryonic stem (mES) cells self-renewal. 1762 Mar 14

Continuous exposure of follicles/oocytes to elevated levels of insulin compromises embryonic developmental competence, although the underlying cellular mechanisms are unknown. The objectives of the present study were to determine whether mouse oocytes have insulin receptors and a functional insulin signaling cascade, and whether insulin exposure during oocyte growth or maturation influences meiotic progression and chromatin remodeling. Immunoblot and immunocytochemical analyses of germinal vesicle-intact (GVI) oocytes demonstrated the presence of insulin receptor-beta. Insulin receptor expression in oocytes was increased by gonadotropin stimulation, and remained elevated throughout meiotic maturation. Fully grown GVI oocytes contained 3-phosphoinositide-dependent protein kinase-1 (PDPK1), thymoma viral proto-oncogene 1 (AKT1), and glycogen synthase kinase 3 (GSK3). In vitro maturation of GVI oocytes in 5 microg/ml insulin had no influence on meiotic progression or the incidence of normal metaphase II (MII) chromosome condensation. Treatment of oocytes during maturation had no effect on GSK3A/B protein expression or phosphorylation of S21/9. However, the culturing of preantral follicles for 10 days with 5 microg/ml insulin increased the phosphorylation of oocyte GSK3B, indicating GSK3 inactivation. The rates of development to metaphase I (MI) were similar for oocytes obtained from insulin-treated follicles and controls, whereas the incidence of abnormal MI chromatin condensation was significantly higher in oocytes obtained from follicles cultured with insulin compared to those cultured without insulin. These results demonstrate that oocytes contain a functional insulin signaling pathway, and that insulin exposure during oocyte growth results in chromatin remodeling aberrations. These findings begin to elucidate the mechanisms by which chronic elevated insulin influences oocyte meiosis, chromatin remodeling, and embryonic developmental competence.
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PMID:Insulin signaling in mouse oocytes. 1762 12

Insulin receptor substrate (IRS)-1 and IRS-2 have dominant roles in the action of insulin, but other substrates of the insulin receptor kinase, such as Gab1, c-Cbl, SH2-B and APS, are also of physiological relevance. Although the protein downstream of tyrosine kinases-1 (Dok1) is known to function as a multisite adapter molecule in insulin signaling, its role in energy homeostasis has remained unclear. Here we show that Dok1 regulates adiposity. Expression of Dok1 in white adipose tissue was markedly increased in mice fed a high-fat diet, whereas adipocytes lacking this adapter were smaller and showed a reduced hypertrophic response to this dietary manipulation. Dok1-deficient mice were leaner and showed improved glucose tolerance and insulin sensitivity compared with wild-type mice. Embryonic fibroblasts from Dok1-deficient mice were impaired in adipogenic differentiation, and this defect was accompanied by an increased activity of the protein kinase ERK and a consequent increase in the phosphorylation of peroxisome proliferator-activated receptor (PPAR)-gamma on Ser112. Mutation of this negative regulatory site for the transactivation activity of PPAR-gamma blocked development of the lean phenotype caused by Dok1 ablation. These results indicate that Dok1 promotes adipocyte hypertrophy by counteracting the inhibitory effect of ERK on PPAR-gamma and may thus confer predisposition to diet-induced obesity.
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PMID:Dok1 mediates high-fat diet-induced adipocyte hypertrophy and obesity through modulation of PPAR-gamma phosphorylation. 1820 60


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