Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Sustained hyperglycemia impairs insulin-stimulated glucose utilization and glycogen synthesis in human and rat skeletal muscles, a phenomenon referred to clinically as glucose toxicity. In rat extensor digitorum longus (EDL) muscle preparations preincubated for 2-4 h in a hyperglycemic medium (25 mM vs. 0 mM glucose), we have shown that the ability of insulin to stimulate glucose incorporation into glycogen is impaired. Interestingly, this was associated with a decreased activation of Akt/PKB, but not its upstream regulator, PI3-kinase. A similar pattern of signaling abnormalities has been observed in adipocytes, L6 muscle cells, C2C12 cells, and (as reported here) EDL incubated with C(2)-ceramide. On the other hand, no increase was observed in ceramide mass in EDL incubated with 25 mM glucose. Hyperglycemia-induced insulin resistance also has been described in adipocytes, where it has been linked to activation of novel and conventional protein kinase C isoforms that phosphorylate the insulin receptor and IRS. In addition, we have recently shown that hyperglycemia causes insulin resistance in cultured human umbilical vein endothelial cells (HUVEC). Here, it was associated with an increased propensity to apoptosis and, as in muscle, with an impaired ability of insulin to activate Akt. Interestingly, these effects of hyperglycemia and an increase in diacylglycerol synthesis, which is also caused, were prevented by adding AICAR, an activator of AMP-activated protein kinase (AMPK), to the incubation medium. These results suggest that hyperglycemia causes insulin resistance in cells other than those in classic insulin target tissues. Whether AMPK activation can reverse or prevent insulin resistance in all of these cells remains to be determined.
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PMID:Hyperglycemia and insulin resistance: possible mechanisms. 1207 34

Chronic leptin treatment markedly enhances the effect of insulin on hepatic glucose production unproportionally with respect to body weight loss and increased insulin sensitivity. In the present study the cross-talk between insulin and leptin was evaluated in rat liver. Upon stimulation of JAK2 tyrosine phosphorylation, leptin induced JAK2 co-immunoprecipitation with STAT3, STAT5b, IRS-1 and IRS-2. This phenomenon parallels the leptin-induced tyrosine phosphorylation of STAT3, STAT5b, IRS-1 and IRS-2. Acutely injected insulin stimulated a mild increase in tyrosine phosphorylation of JAK2, STAT3 and STAT5b. Leptin was less effective than insulin in stimulating IRS phosphorylation and their association with PI 3-kinase. Simultaneous treatment with both hormones yielded no change in maximal phosphorylation of STAT3, IRS-1, IRS-2 and Akt, but led to a marked increase in tyrosine phosphorylation of JAK2 and STAT5b when compared with isolated administration of insulin or leptin. This indicates that there is a positive cross-talk between insulin and leptin signaling pathways at the level of JAK2 and STAT5b in rat liver.
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PMID:Interaction between leptin and insulin signaling pathways differentially affects JAK-STAT and PI 3-kinase-mediated signaling in rat liver. 1267 9

IRS-2 plays an important role in the control of pancreatic beta-cell growth, however it is unclear if other IRS family members are also involved. Using recombinant adenoviruses, IRS-1, -2 and -3 expression was varied in the beta-cell line, INS-1. Increased IRS-1 expression had no appreciable effect on beta-cell growth. However, increased IRS-2 expression augmented glucose/IGF-1 induced beta-cell growth mitogenesis and decreased apoptosis due to glucose-deprivation. In contrast, increased IRS-3 expression significantly inhibited mitogenesis and increased apoptosis. IRS-3 was intransiently located to the beta-cell plasma membrane, and appeared to be inert in terms of IGF-1 induced signaling. However, increased IRS-3 expression blocked glucose/IGF-1 induced IRS-2 translocation from the cytosol to the plasma membrane, dampening IRS-2/IGF-1R interaction and subsequent activation of the PI3K/PKB/GSK3 signaling pathway. In contrast, glucose/IGF-1 induced Erk-1/-2 and p70S6K activation were unaffected by IRS-3. These data emphasize the importance of IRS-2/PI3K/PKB signal transduction for beta-cell growth and survival.
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PMID:IRS-3 inhibits IRS-2-mediated signaling in pancreatic beta-cells. 1285 Feb 84

Insulin and angiotensin II (AngII) may act through overlapping intracellular pathways to promote cardiac myocyte growth. In this report insulin and AngII signaling, through the phosphatidylinositol 3-kinase (PI 3-kinase) and MAPK pathways, were compared in cardiac tissues of control and obese Zucker rats. AngII induced Janus kinase 2 tyrosine phosphorylation and coimmunoprecipitation with insulin receptor substrate 1 (IRS-1) and IRS-2 as well as an increase in tyrosine phosphorylation of IRS and its association with growth factor receptor-binding protein 2. Simultaneous treatment with both hormones led to marked increases in the associations of IRS-1 and -2 with growth factor receptor-binding protein 2 and in the dual phosphorylation of ERK1/2 compared with the administration of AngII or insulin alone. In contrast, an acute inhibition of both basal and insulin-stimulated PI 3-kinase activity was induced by both hormones. Insulin stimulated the phosphorylation of MAPK equally in lean and obese rats. Conversely, insulin-induced phosphorylation of Akt in heart was decreased in obese rats. Pretreatment with losartan did not change insulin-induced activation of ERK1/2 and attenuated the reduction of Akt phosphorylation in the heart of obese rats. Thus, the imbalance between PI 3-kinase-Akt and MAPK signaling pathways in the heart may play a role in the development of cardiovascular abnormalities observed in insulin-resistant states, such as in obese Zucker rats.
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PMID:The cross-talk between angiotensin and insulin differentially affects phosphatidylinositol 3-kinase- and mitogen-activated protein kinase-mediated signaling in rat heart: implications for insulin resistance. 1296 6

Nonenzymatic glycation is increased in diabetes and leads to increased levels of glycated proteins. Most studies have focused on the role of glycation products in vascular complications. Here, we have investigated the action of human glycated albumin (HGA) on insulin signaling in L6 skeletal muscle cells. Exposure of these cells to HGA inhibited insulin-stimulated glucose uptake and glycogen synthase activity by 95 and 80%, respectively. These effects were time- and dose-dependent, reaching a maximum after 12 h incubation with 0.1 mg/ml HGA. In contrast, exposure of the cells to HGA had no effect on thymidine incorporation. Further, HGA reduced insulin-stimulated serine phosphorylation of PKB and GSK3, but did not alter ERK1/2 activation. HGA did not affect either insulin receptor kinase activity or insulin-induced Shc phosphorylation on tyrosine. In contrast, insulin-dependent IRS-1 and IRS-2 tyrosine phosphorylation was severely reduced in cells preincubated with HGA for 24 h. Insulin-stimulated association of PI3K with IRS-1 and IRS-2, and PI3K activity were reduced by HGA in parallel with the changes in IRS tyrosine phosphorylation, while Grb2-IRS association was unchanged. In L6 myotubes, exposure to HGA increased PKC activity by 2-fold resulting in a similar increase in Ser/Thr phosphorylation of IRS-1 and IRS-2. These phosphorylations were blocked by the PKC inhibitor bisindolylmaleimide (BDM). BDM also blocked the action of HGA on insulin-stimulated PKB and GSK3 alpha. Simultaneously, BDM rescued insulin-stimulation of glucose uptake and glycogen synthase activity in cells exposed to HGA. The use of antibodies specific to PKC isoforms shows that this effect appears to be mediated by activated PKC alpha, independent of reactive oxygen species production. In summary, in L6 skeletal muscle cells, exposure to HGA leads to insulin resistance selectively in glucose metabolism with no effect on growth-related pathways regulated by the hormone.
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PMID:Human glycated albumin affects glucose metabolism in L6 skeletal muscle cells by impairing insulin-induced insulin receptor substrate (IRS) signaling through a protein kinase C alpha-mediated mechanism. 1297 Mar 60

Adipose tissue is a primary target of insulin, but knowledge about insulin signalling in human adipocytes is limited. We developed an electroporation technique for transfection of primary human adipocytes with a transfection efficiency of 15% +/- 5 (mean +/- S.D.). Human adipocytes were co-transfected with a mutant of IRS-3 (all four potential PI3-kinase binding motifs mutated: IRS-3F4) and HA-tagged protein kinase B (HA-PKB/Akt). HA-PKB/Akt was immunoprecipitated from cell lysates with anti-HA antibodies, resolved with SDS-PAGE, and immunoblotted with phospho-specific antibodies. We found that IRS-3F4 blocked insulin stimulation of HA-PKB/Akt phosphorylation and in further analyses also translocation of recombinant HA-tagged glucose transporter to the plasma membrane. IRS-3F4 also blocked insulin-induced activation of the transcription factor Elk-1. Our results demonstrate the critical importance of IRS for metabolic as well as mitogenic signalling by insulin. This method for transfection of primary human adipocytes will be useful for studying insulin signalling in human adipocytes with molecular biological techniques.
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PMID:Expression of a mutant IRS inhibits metabolic and mitogenic signalling of insulin in human adipocytes. 1522 27

IL-9 is a multifunctional cytokine secreted by TH2 lymphocytes. Besides its role during immune responses, its growth factor and antiapoptotic activities on multiple transformed cells suggest a potential role in tumorigenesis. Indeed, IL-9 overexpression induces thymic lymphomas in mice, and IL-9 production is associated with Hodgkin disease and HTLV-I transformed T cells in humans. IL-9 activities are mediated by a specific receptor chain that forms a heterodimeric receptor with the common gamma chain also involved in IL-2,4,7,15 and 21 signaling. The IL-9 receptor and common gamma chains associate with JAK1 and JAK3, respectively and trigger the STAT-1, -3 and -5, IRS and RAS-MAPK pathways. Moreover, in vitro, dysregulated IL-9 response can lead to autonomous cell growth and malignant transformation of lymphoid cells associated with constitutive activation of the Jak/STAT pathway.
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PMID:IL-9 and its receptor: from signal transduction to tumorigenesis. 1562 23

This review will provide insight on the current understanding of the regulation of insulin signaling in both physiological and pathological conditions through modulations that occur with regards to the functions of the insulin receptor substrate 1 (IRS1). While the phosphorylation of IRS1 on tyrosine residue is required for insulin-stimulated responses, the phosphorylation of IRS1 on serine residues has a dual role, either to enhance or to terminate the insulin effects. The activation of PKB in response to insulin propagates insulin signaling and promotes the phosphorylation of IRS1 on serine residue in turn generating a positive-feedback loop for insulin action. Insulin also activates several kinases and these kinases act to induce the phosphorylation of IRS1 on specific sites and inhibit its functions. This is part of the negative-feedback control mechanism induced by insulin that leads to termination of its action. Agents such as free fatty acids, cytokines, angiotensin II, endothelin-1, amino acids, cellular stress and hyperinsulinemia, which induce insulin resistance, lead to both activation of several serine/threonine kinases and phosphorylation of IRS1. These agents negatively regulate the IRS1 functions by phosphorylation but also via others molecular mechanisms (SOCS expression, IRS degradation, O-linked glycosylation) as summarized in this review. Understanding how these agents inhibit IRS1 functions as well as identification of kinases involved in these inhibitory effects may provide novel targets for development of strategies to prevent insulin resistance.
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PMID:Positive and negative regulation of insulin signaling through IRS-1 phosphorylation. 1573 44

Growth hormone (GH) exerts many effects in addition to its ability to stimulate growth. The metabolic effects are either chronic diabetogenic or acute insulin-like. The latter effects are only seen in cells that have been deprived of the hormone for a few hours. After exposure to GH the ability of the cells to respond with insulin-like effects disappears within a couple of hours, a negative feedback loop, which is a part of the chronic effects of the hormone. The insulin-like effects are mediated by the cytosolic tyrosine kinase Janus kinase 2 (JAK2) upon GH-GH receptor interaction, resulting in tyrosine phosphorylation of downstream targets including the GH receptor itself and insulin receptor substrate-1 (IRS-1) and IRS-2. Analogous to the post-receptor events for insulin this results in recruitment of phosphatidylinositol-3 kinase (PI3-kinase) to the IRS-proteins. Downstream PI3-kinase protein kinase B/Akt participates in the activation of glucose transporters (GLUT4) and increased glucose uptake as well as activation of phosphodiesterase 3B and hydrolysis of cAMP leading to a net dephosphorylation of the hormone sensitive lipase and inhibition of lipolysis. Simultaneously, JAK2 phosphorylates STAT-family transcription factors that move into the nucleus and activate the transcription of, among others, genes coding for negatively regulatory proteins called Suppressors of cytokine signalling (SOCS). The turnover of SOCS is rapid and in their presence JAK2 will still activate STAT-proteins (and the diabetogenic effects), but no longer phosphorylate the IRS-proteins (and induce insulin-like effects), closing the loop of yet another classical hormonal negative feedback loop.
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PMID:Signaling mechanism for the insulin-like effects of growth hormone--another example of a classical hormonal negative feedback loop. 1577 7

Obesity, a state of apparent "leptin resistance" is well known to be associated with insulin resistance. In diet-induced obesity (DIO), hepatic insulin signaling is impaired but the link between leptin and insulin signaling pathways is only incompletely defined. The aim of the present study was to evaluate the effects of DIO on leptin and insulin cross-signaling in the liver. Leptin receptor expression was measured by in situ hybridization with pan-leptin receptor probes and by immunoblotting. Furthermore, intracellular signaling was investigated in vivo under basal conditions and at 45 and 360 min after stimulation with a bolus of human recombinant leptin (hrec-leptin; 1 mg/kg body wt) or saline. At baseline, all forms of the leptin receptor were markedly to completely down-regulated in DIO rats. Hrec-leptin bolus injection stimulated leptin-dependent signaling with a fivefold increase in JAK-2pY in lean but not in DIO rats. Basal IRpY, IRS-1pY, IRS-1p85, IRS-2pY, IRSp85, and PKBpT308 levels were reduced (P<0.01) in DIO rats as compared with lean controls. Basal GSK-3beta serine phosphorylation (S9) was higher (P<0.01) in lean animals along with lower basal PEPCK activity compared with DIO rats consistent with the insulin and leptin resistance of the latter. Only in lean animals phosphorylation of PKB (T308) and GSK-3beta (S9) was acutely stimulated by leptin at 45 min followed by inhibition at 6 h after application. AMPKalpha protein levels as well as basal and leptin-stimulated total and alpha-specific AMPK activity were comparable in both groups. These data show that in a model of dietary-induced obesity 1) leptin receptors and subsequent signaling events are down-regulated, 2) basal insulin signaling is impaired, and 3) the cross-talk between leptin and insulin signaling is differentially regulated by the nutritional status, which is sensed by AMPK in rat liver. Thus, the liver seems to play a major role in the modulation of the leptin signal and insulin resistance in obesity.
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PMID:Hepatic leptin signaling in obesity. 1578 47


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