Novel mechanisms of growth regulation through changes in ubiquitination of insulin receptor substrates

胰岛素样生长因子(IGF)- 1受体酪氨酸激酶磷酸化的胰岛素受体底物（IRSs）。磷酸化酪氨酸基IRSs被具有SH2结构域的信号分子识别，而SH2结构域介导各种IGF的生物活性。然而，我们已经证明IRSs也通过不依赖于磷酸酪氨酸的机制与其他蛋白质结合。这些蛋白复合物含有许多泛素连接酶（E3）和去泛素化酶（DUBs）。我们的研究结果表明，受这些E3和dub对其他细胞外因子的动态调控的IRSs泛素化不仅在调节其蛋白水平方面发挥重要作用，而且还调节其酪氨酸磷酸化，从而控制IGF的生物活性，如促生长活性。

Insulin receptor substrates (IRSs) that are phosphorylated by insulin-like growth factor (IGF)-I receptor tyrosine kinases. Phosphotyrosyl IRSs are recognized by signaling molecules possessing SH2 domains, which mediate various IGF bioactivities. However, we have shown that IRSs are also associated with other proteins by a phosphotyrosine-independent mechanism. These protein complexes contain a number of ubiquitin ligases (E3) and deubiquitinating enzymes (DUBs). Our results indicate that ubiquitination of IRSs which was dynamically regulated by these E3 and DUBs in response to other extracellular factor, plays important roles not only in regulation of their protein levels but also modulation of their tyrosine phosphorylation, leading to control of IGF bioactivities, such as a growth-promoting activity.