Identification of Tyrosine Phosphatases That Dephosphorylate the Insulin Receptor

Wälchli, Sébastien; Curchod, Marie Laure; Gobert, Rosanna Pescini; Arkinstall, Steve; Huijsduijnen, Rob Hooft van

doi:10.1074/jbc.275.13.9792

Cited by 159 publications

(100 citation statements)

References 36 publications

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“…Rat adipose cells overexpressing PTP␣ showed significantly lower insulin-stimulated levels of cell surface GLUT4 and a 3-fold decrease in insulin sensitivity (9). Although, in the first study (7), PTP␣ overexpression decreased insulin receptor Tyr phosphorylation, the demonstration that the insulin receptor is a substrate of PTP␣ has not been a consistent finding (8,10).…”

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confidence: 75%

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The Differentiation of Skeletal Muscle Cells Involves a Protein-tyrosine Phosphatase-α-mediated C-Src Signaling Pathway

Shah

Ennis

et al. 2002

Journal of Biological Chemistry

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confidence: 75%

“…Several studies have suggested that it acts as an inhibitor of insulin signaling (7,47,48), yet other reports have not confirmed these actions (8,10). We sought to investigate this hypothesis in skeletal muscle, a major insulin target tissue, and employed the rat skeletal muscle cell line L6.…”

Section: Discussionmentioning

confidence: 99%

The Differentiation of Skeletal Muscle Cells Involves a Protein-tyrosine Phosphatase-α-mediated C-Src Signaling Pathway

Shah

Ennis

et al. 2002

Journal of Biological Chemistry

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“…The acute regulation of eNOS was monitored through association with HSP-90 and protein phosphorylation of T494, S632, and S1176. Finally, an in vitro model of insulin resistance was induced in endothelial cells via adenoviral expression of protein tyrosine phosphatase (PTP) 1B (51). Regardless of the model, eNOS expression, phosphorylation, or binding to HSP-90 was undiminished.…”

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confidence: 99%

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

Fulton

Harris

Kemp

et al. 2004

American Journal of Physiology-Heart and Circulatory Physiology

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.-Previously, using an animal model of syndrome X, the obese Zucker rat (OZR), we documented impaired endothelium-dependent vasodilation. The aim of this study was to determine whether reduced expression or altered posttranslational regulation of endothelial nitric oxide synthase (eNOS) underlies the vascular dysfunction in OZR rats. There was no significant difference in the relative abundance of eNOS in hearts, aortas, or skeletal muscle between lean Zucker rats (LZR) and OZR regardless of age. There was no difference in eNOS mRNA levels, as determined by real-time PCR, between LZR and OZR. The inability of insulin resistance to modulate eNOS expression was also documented in two additional in vivo models, the ob/ob mouse and the fructose-fed rat, and in vitro via adenoviral expression of protein tyrosine phosphatase 1B in endothelial cells. We next investigated whether changes in the acute posttranslational regulation of eNOS occurs with insulin resistance. Phosphorylation of eNOS at S632 (human S633) and T494 was not different between LZR and OZR; however, phosphorylation of S1176 was significantly enhanced in OZR. Phosphorylation of S1176 was not different in the ob/ob mouse or in fructose-fed rats. The association of heat shock protein 90 with eNOS, a key regulatory step controlling nitric oxide and aberrant O 2 Ϫ production, was not different between OZR and LZR. Taken together, these results suggest that changes in eNOS expression or posttranslation regulation do not underlie the vascular dysfunction seen with insulin resistance and that other mechanisms, such as altered localization, reduced availability of cofactors, substrates, and the elevated production of O 2 Ϫ , may be responsible. syndrome X; Zucker; obesity INSULIN RESISTANCE, a prediabetic condition associated with obesity, is increasing at an alarming rate in Western cultures (26,30). Diabetes increases the incidence of many vasculopathies, including atherosclerosis, microvascular disease, and poor wound healing (44, 47). Of even greater concern is the mounting evidence that insulin-resistant states, independent of frank diabetes, also promote vascular dysfunction (43, 52). Thus the effect of insulin resistance on vascular signaling mechanisms is an area of increasing scrutiny. Insulin-resistant states and diabetes are associated with reduced endothelium-dependent relaxation, and this dysfunction of the endothelium is highly correlated with future cardiovascular events (1,14,34,49). In the obese Zucker rat (OZR), we previously showed that endothelium-dependent relaxation is impaired (14); however, the mechanisms underlying reduced synthesis or action of nitric oxide (NO) remain to be established.Endothelium-dependent relaxation is mediated by the synthesis and subsequent diffusion of NO from the endothelium to the underlying smooth muscle (21, 35). Of the three NO synthases (NOS), the endothelial isoform (eNOS) is uniquely positioned within the vascular endothelium and alone is responsible for endothelium-dependent NO-mediated relaxation (20)....

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“…18,19 Received Moreover, a recent study has shown that a related enzyme, PTP-PEST, has the capacity to dephosphorylate a tyrosinephosphorylated oligo peptide sequence based on the insulin receptor. 20 These findings prompted us to test the hypothesis that NO inhibits the cell motility-stimulatory effect of insulin in aortic smooth muscle cells via a mechanism mediated by PTP1B and/or PTP-PEST. We now report that PTP1B is necessary and sufficient to account for the capacity of NO to attenuate insulin-stimulated cell motility.…”

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NO Attenuates Insulin Signaling and Motility in Aortic Smooth Muscle Cells via Protein Tyrosine Phosphatase 1B–Mediated Mechanism

Nair

Yan

Hassid

2002

ATVB

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Objective-Hyperinsulinemia is a significant risk factor for the pathogenesis of vascular disease. Protein tyrosine phosphatase 1B (PTP1B) has been recognized as a modulator of insulin signaling in nonvascular cells, and we have recently reported that NO increases the activity of PTP1B in rat vascular smooth muscle cells. In the present study, we tested the hypothesis that NO attenuates insulin-stimulated cell motility via a PTP1B-mediated mechanism involving downregulation of insulin signal transduction. Methods and Results-Treatment of primary aortic smooth muscle cells from newborn rats with the NO donor S-nitroso-N-acetylpenicillamine reduced cell motility, tyrosine phosphorylation levels of insulin receptor ␤ subunit and insulin receptor substrate-1, and extracellular signal-regulated kinase activity. Overexpression of wild-type PTP1B via an adenoviral vector blocked the capacity of insulin to stimulate cell motility and insulin receptor phosphorylation, whereas expression of a dominant-negative mutant of PTP1B attenuated the capacity of NO to decrease cell motility. Conclusions-Our findings indicate that activation of PTP1B is necessary and sufficient to account for the capacity of NO to decrease insulin-stimulated signal transduction and cell motility in cultured aortic smooth muscle cells. The results could explain the capacity of NO to oppose neointima formation in states of hyperinsulinemia. Key Words: cell signaling Ⅲ signal transduction Ⅲ atherosclerosis Ⅲ growth factors Ⅲ type 2 diabetes T ype II diabetes is a major risk factor for the pathogenesis of vascular disease, including that associated with hypertension and atherosclerosis. That diabetes increases the frequency of coronary vessel restenosis occurring after angioplasty is also well established. 1 Most forms of vascular disease in conduit arteries manifest neointimal enlargement, and although type II diabetes is associated with hyperglycemia as well as hyperinsulinemia, recent studies have suggested that elevated insulin levels may be the more important factor in the pathogenesis of neointimal enlargement. 2,3 The proliferation and motility of vascular smooth muscle cells is regulated in reciprocal fashion by stimulators (eg, fibroblast growth factor, platelet-derived growth factor, and heparin-binding epidermal growth factor) and inhibitors of mitogenesis or motility (eg, prostanoids, heparin, atrial natriuretic factor, and transforming growth factor-␤). 4 -7 Similar to many other growth factors, insulin has the capacity to stimulate cell motility in vitro, which could explain the pathogenesis of diabetic neointimal growth. 3,8 Early studies from several laboratories, including ours, have reported that NO decreases vascular smooth muscle cell proliferation in subcultured cells from adult rats or in primary cultures from newborn rats. 9,10 More recent studies have reported that NO also inhibits aortic smooth muscle cell motility. 11,12 Furthermore, several studies in vivo have reported that NO, or its precursor arginine, attenuates neointima ...

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Identification of Tyrosine Phosphatases That Dephosphorylate the Insulin Receptor

Cited by 159 publications

References 36 publications

The Differentiation of Skeletal Muscle Cells Involves a Protein-tyrosine Phosphatase-α-mediated C-Src Signaling Pathway

The Differentiation of Skeletal Muscle Cells Involves a Protein-tyrosine Phosphatase-α-mediated C-Src Signaling Pathway

Insulin resistance does not diminish eNOS expression, phosphorylation, or binding to HSP-90

NO Attenuates Insulin Signaling and Motility in Aortic Smooth Muscle Cells via Protein Tyrosine Phosphatase 1B–Mediated Mechanism

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