Insulin receptor substrate 2 ( IRS - 2 ) plays diverse cell - specific roles in the regulation of glucose transport

The insulin receptor substrate 2 (IRS-2) protein is one of the major insulinsignaling substrates. In the present study, we investigated the role of IRS-2 in skin epidermal keratinocytes and dermal fibroblasts. Even though skin is not a classical insulin target tissue, we have previously demonstrated that insulin, via the insulin receptor (IR), is essential for normal skin cell physiology. To identify the role of IRS-2 in skin cells, we studied cells isolated from IRS-2 knockout (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 phosphatidyl inositol (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. 3 by gest on July 5, 2017 hp://w w w .jb.org/ D ow nladed from IRS-2 diverse regulation of glucose transport in skin cells