| First Author | Sadagurski M | Year | 2005 |
| Journal | J Biol Chem | Volume | 280 |
| Issue | 15 | Pages | 14536-44 |
| PubMed ID | 15705592 | Mgi Jnum | J:107134 |
| Mgi Id | MGI:3620335 | Doi | 10.1074/jbc.M410227200 |
| Citation | Sadagurski M, et al. (2005) Insulin receptor substrate 2 plays diverse cell-specific roles in the regulation of glucose transport. J Biol Chem 280(15):14536-44 |
| abstractText | 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. |
