Insulin Receptor Substrate 2 Plays Diverse Cell-specific Roles in the Regulation of Glucose Transport

Marianna Sadagurski,Galina Weingarten,Christopher J Rhodes,Morris F White,Efrat Wertheimer

doi:10.1074/jbc.m410227200

Abstract

The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates. In the present study, we investigated the role of IRS-2 in skin epidermal keratinocytes and dermal fibroblasts. Although skin is not a classical insulin target tissue, we have previously demonstrated that insulin, via the insulin receptor, is essential for normal skin cell physiology. To identify the role of IRS-2 in skin cells, we studied cells isolated from IRS-2 knock-out (KO) mice. Whereas proliferation and differentiation were not affected in the IRS-2 KO cells, a striking effect was observed on glucose transport. In IRS-2 KO keratinocytes, the lack of IRS-2 resulted in a dramatic increase in basal and insulin-stimulated glucose transport. The increase in glucose transport was associated with an increase in total phosphatidylinositol (PI) 3-kinase and Akt activation. In contrast, fibroblasts lacking IRS-2 exhibited a significant decrease in basal and insulin-induced glucose transport. We identified the point of divergence, leading to these differences between keratinocytes and fibroblasts, at the IRS-PI 3-kinase association step. In epidermal keratinocytes, PI 3-kinase is associated with and activated by only the IRS-1 protein. On the other hand, in dermal fibroblasts, PI 3-kinase is exclusively associated with and activated by the IRS-2 protein. These observations suggest that IRS-2 functions as a negative or positive regulator of glucose transport in a cell-specific manner. Our results also show that IRS-2 function depends on its cell-specific association with PI 3-kinase.

Highlights

The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates
Our results clearly demonstrate that the role of IRS-2 in mediating insulin-induced glucose transport is divergent in the skin epidermal keratinocyte and dermal fibroblasts
There was only a slight increase in the expression and insulin-induced activation of IRS-1 protein in both IRS-2 KO cell types. These results suggest that there is only a partial compensatory mechanism of insulin-induced IRS-1 activation in skin cells lacking IRS-2 expression

Summary

Introduction

The insulin receptor substrate 2 (IRS-2) protein is one of the major insulin-signaling substrates. In dermal fibroblasts, PI 3-kinase is exclusively associated with and activated by the IRS-2 protein These observations suggest that IRS-2 functions as a negative or positive regulator of glucose transport in a cell-specific manner. It has been found that deleting IR in neurons results in increased food intake and moderate diet-dependent obesity as well as impaired spermatogenesis and ovarian follicle maturation due to the hypothalamic dysregulation of luteinizing hormone [3] These surprising observations raise a question as to the molecular basis behind the different effects of insulin among the various tissues, especially among the nonclassical insulin target tissues. IRS-2-deficient mice showed progressive deterioration of glucose homeostasis and developed diabetes [7] From these findings, it is clear that the IRSs are essential in mediating the specific metabolic roles of insulin in the classical insulin target tissues and that they participate in insulin-regulated processes in other tissues as well

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