Glucose-induced phosphorylation of the insulin receptor. Functional effects and characterization of phosphorylation sites.

Pillay, Tahir S; Xiao, Sen; Olefsky, Jerrold M.

doi:10.1172/jci118457

Cited by 74 publications

(57 citation statements)

References 49 publications

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“…Previous studies clearly showed that an increase in IR and IRSs serine phosphorylation could induce insulin resistance, pointing to this as an important mechanism in the control of insulin signalling [45,46,47]. It has been reported that activation of PKC induces serine phosphorylation of IR, which can inhibit its tyrosine kinase activity, leading to a decrease in insulin-induced PI3-kinase activity [48,49].…”

Section: Discussionmentioning

confidence: 99%

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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Aim/hypothesis. By acting in the brain, insulin suppresses food intake. However, little is known with regard to insulin signalling in the hypothalamus in insulin-resistant states. Methods. Western blotting, immunohistochemistry and polymerase chain reaction assays were combined to compare in vivo hypothalamic insulin signalling through the PI3-kinase and MAP kinase pathways between lean and obese Zucker rats. Results. Intracerebroventricular insulin infusion reduced food intake in lean rats to a greater extent than that observed in obese rats, and pre-treatment with PI3-kinase inhibitors prevented insulin-induced anorexia. The relative abundance of IRS-2 was considerably higher than that of IRS-1 in hypothalamus of both lean and obese rats. Insulin-stimulated phosphorylation of IR, IRS-1/2, the associations of PI 3-kinase to IRS-1/2 and phosphorylation of Akt in hypothalamus were decreased in obese rats compared to lean rats. These effects seem to be mediated by increased phosphoserine content of IR, IRS-1/2 and decreased protein levels of IRS-1/2 in obese rats. In contrast, insulin stimulated the phosphorylation of MAP kinase equally in lean and obese rats. Conclusion/interpretation. This study provides direct measurements of insulin signalling in hypothalamus, and documents selective resistance to insulin signalling in hypothalamus of Zucker rats. These findings provide support for the hypothesis that insulin could have anti-obesity actions mediated by the PI3-kinase pathway, and that impaired insulin signalling in hypothalamus could play a role in the development of obesity in this animal model of insulin-resistance. [Diabetologia (2003[Diabetologia ( ) 46:1629[Diabetologia ( -1640 Keywords Obesity, insulin resistance, hypothalamus, anorexia, signal transduction, phosphatidylinositol 3-kinase/antagonists & inhibitors/*metabolism, mitogen-activated protein kinase. Abbreviations: ERK, extracellular signal-regulated kinase; Grb2, growth factor receptor binding protein 2; IR, insulin receptor; IRS, insulin receptor substrate; MAPK, mitogen-activated protein kinase; PI 3-kinase, phosphatidylinositol 3-kinase; PKC, Protein kinase C; Shc, Src-homology and collagen homology; SHP2, Src-homology phosphatase 2; TNF-α, Tumor-necrosis factor-α.

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Section: Discussionmentioning

confidence: 99%

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

et al. 2003

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“…The impairment of insulin receptor substrate-1 tyrosine phosphorylation is greater than that of the insulin receptor, resulting in attenuated phosphatidylinositol 3-kinase activation and mitogenic signalling. 30 Other studies indicated that high glucose inhibited hypoxia-induced VEGF response in cultured proximal tubular cells at both mRNA and protein levels. 31 Besides, high glucose was also reported to inhibit insulin-stimulated nitric oxide production by impairing molecular (IRS-1, PI 3-kinase) and functional insulin signals in vascular endothelial cells.…”

Section: Discussionmentioning

confidence: 99%

High glucose attenuates insulin-induced VEGF expression in bovine retinal microvascular endothelial cells

Xia

Jiang

et al. 2009

Eye

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“…Upon stimulation tyrosine phosphorylated YXXM motifs associate with SH2 domains of p85 (51), and the engagement of p85 SH2 domain relieves the p85-mediated inhibition of p110 thus increasing the enzymatic activity of p110 (17). However, with hyperglycemia there is a major decrease in IRS-1 tyrosine phosphorylation (5,52,53), and hyperglycemia mediates IRS-1 degradation (23,54), which leads to a decrease in IRS-1-mediated PI3K activation (8,23,25). IRS-1 repression has been shown to induce a substantial increase in Shc expression and its tyrosine phosphorylation in response to insulin, and it has been proposed that in the absence of IRS-1 enhanced Shc phosphorylation could represent an alternative pathway to transduce insulin signaling (55,56).…”

Section: Discussionmentioning

confidence: 99%

Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells

Radhakrishnan¹,

Maile²,

Ling³

et al. 2008

Journal of Biological Chemistry

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Insulin-like growth factor-I (IGF-I) stimulates vascular smooth muscle cell proliferation and migration by activating both MAPK and phosphatidylinositol 3-kinase (PI3K). Vascular smooth muscle cells (VSMCs) maintained in 25 mM glucose sustain MAPK activation via increased Shc phosphorylation and Grb2 association resulting in an enhanced mitogenic response compared with cells grown in 5 mM glucose. PI3K plays a major role in IGF-I-stimulated VSMC migration, and hyperglycemia augments this response. In contrast to MAPK activation the role of Shc in modulating PI3K in response to IGF-I has not been determined. In this study we show that impaired Shc association with Grb2 results in decreased Grb2-p85 association, SHPS-1-p85 recruitment, and PI3K activation in response to IGF-I. Exposure of VSMCs to cell-permeable peptides, which contained polyproline sequences from p85 proposed to mediate Grb2 association, resulted in inhibition of Grb2-p85 binding and AKT phosphorylation. Transfected cells that expressed p85 mutant that had specific prolines mutated to alanines resulted in less Grb2-p85 association, and a Grb2 mutant (W36A/ W193A) that attenuated p85 binding showed decreased association of p85 with SHPS-1, PI3K activation, AKT phosphorylation, cell proliferation, and migration in response to IGF-I. Cellular exposure to 25 mM glucose, which is required for Shc phosphorylation in response to IGF-I, resulted in enhanced Grb2 binding to p85, activation of PI3K activity, and increased AKT phosphorylation as compared with cells exposed to 5 mM glucose. We conclude that in VSMCs exposed to hyperglycemia, IGF-I stimulation of Shc facilitates the transfer of Grb2 to p85 resulting in enhanced PI3K activation and AKT phosphorylation leading to enhanced cell proliferation and migration. Insulin-like growth factor-I (IGF-I)2 stimulates proliferation and migration in vascular smooth muscle cells (VSMCs) (1). IGF-I-stimulated VSMC migration and/or proliferation requires ligand occupancy of the ␣V␤3 integrin (2). Activation of the IGF-I receptor is coupled to downstream signaling events via recruitment and phosphorylation of two major adaptor proteins, Shc or members of the insulin receptor substrate (IRS) family. In VSMCs IGF-I stimulation leads to recruitment of the signaling protein Shc to SHP substrate-1 (SHPS-1) allowing sustained MAPK activation (3). IGF-I stimulation of phosphatidylinositol 3-kinase (PI3K) is also required to induce VSMC migration (4). Hyperglycemia has been shown to increase the responsiveness of smooth muscle cells as well as other cell types to growth factor stimulation (5-9). Following IGF-I stimulation of porcine VSMCs maintained in hyperglycemic conditions (e.g. Ͼ12 mM glucose) there is an increase in Shc phosphorylation and subsequent Grb2 association resulting in sustained MAPK activation and enhanced cell proliferation. In contrast cells grown in 5 mM glucose do not show these changes (5). Mutation of three Shc tyrosine phosphorylation sites, Tyr-239/ 240/317, that are required for Grb2 associatio...

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Glucose-induced phosphorylation of the insulin receptor. Functional effects and characterization of phosphorylation sites.

Cited by 74 publications

References 49 publications

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

Selective impairment of insulin signalling in the hypothalamus of obese Zucker rats

High glucose attenuates insulin-induced VEGF expression in bovine retinal microvascular endothelial cells

Insulin-like Growth Factor-I Stimulates Shc-dependent Phosphatidylinositol 3-Kinase Activation via Grb2-associated p85 in Vascular Smooth Muscle Cells

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