Araki E, Lipes M A, Patti M E, Brüning J C, Haag B, Johnson R S, Kahn C R
Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215.
Nature. 1994 Nov 10;372(6502):186-90. doi: 10.1038/372186a0.
The principal substrate for the insulin and insulin-like growth factor-1 (IGF-1) receptors is the cytoplasmic protein insulin-receptor substrate-1 (IRS-1/pp185). After tyrosine phosphorylation at several sites, IRS-1 binds to and activates phosphatidylinositol-3'-OH kinase (PI(3)K) and several other proteins containing SH2 (Src-homology 2) domains. To elucidate the role of IRS-1 in insulin/IGF-1 action, we created IRS-1-deficient mice by targeted gene mutation. These mice had no IRS-1 and showed no evidence of IRS-1 phosphorylation or IRS-1-associated PI(3)K activity. They also had a 50 per cent reduction in intrauterine growth, impaired glucose tolerance, and a decrease in insulin/IGF-1-stimulated glucose uptake in vivo and in vitro. The residual insulin/IGF-1 action correlated with the appearance of a new tyrosine-phosphorylated protein (IRS-2) which binds to PI(3)K, but is slightly larger than and immunologically distinct from IRS-1. Our results provide evidence for IRS-1-dependent and IRS-1-independent pathways of insulin/IGF-1 signalling and for the existence of an alternative substrate of these receptor kinases.
胰岛素及胰岛素样生长因子-1（IGF-1）受体的主要底物是细胞质蛋白胰岛素受体底物-1（IRS-1/pp185）。在多个位点发生酪氨酸磷酸化后，IRS-1与磷脂酰肌醇-3'-OH激酶（PI(3)K）及其他几种含有SH2（Src同源2）结构域的蛋白结合并激活它们。为阐明IRS-1在胰岛素/IGF-1作用中的角色，我们通过靶向基因突变创建了IRS-1缺陷小鼠。这些小鼠没有IRS-1，也没有IRS-1磷酸化或与IRS-1相关的PI(3)K活性的证据。它们在子宫内的生长也减少了50%，糖耐量受损，并且在体内和体外胰岛素/IGF-1刺激的葡萄糖摄取均减少。残余的胰岛素/IGF-1作用与一种新的酪氨酸磷酸化蛋白（IRS-2）的出现相关，该蛋白与PI(3)K结合，但比IRS-1略大且在免疫上与IRS-1不同。我们的结果为胰岛素/IGF-1信号传导的IRS-1依赖性和IRS-1非依赖性途径以及这些受体激酶存在替代底物提供了证据。
