Caveolin is an activator of insulin receptor signaling
Caveolin is an activator of insulin receptor signaling
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DOI：
10.1074/jbc.273.41.26962
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发表时间：
1998-10-09
影响因子：
4.8
通讯作者：
Ishikawa, Y
中科院分区：
文献类型：
--
作者：
Yamamoto, M;Toya, Y;Ishikawa, Y
最近的研究表明，小窝蛋白是小窝的主要结构蛋白，它对小窝内的信号分子具有负调控作用。小窝蛋白与几种小窝相关信号蛋白的相互作用是通过小窝蛋白的支架区与被调控蛋白内的疏水氨基酸区的结合来介导的。我们发现小窝蛋白-3的过表达增强了胰岛素刺激的293 T细胞胰岛素受体底物-1的磷酸化，但对胰岛素受体的磷酸化没有影响。与小窝蛋白的支架结构域相对应的肽在体外以小窝蛋白亚型依赖的方式有力地刺激胰岛素受体激酶对胰岛素受体底物-1或Src衍生肽的活性。来自小窝蛋白-2的肽没有表现出效果，而小窝蛋白-1和-3分别刺激活性10倍和17倍。增加胰岛素受体激酶活性的肽在不影响胰岛素受体自身磷酸化的情况下这样做。此外，胰岛素受体结合到固定的小窝蛋白肽，这种结合在自由小窝蛋白-3肽的存在下被抑制。因此，我们已经确定了一种新的机制，通过这种机制，胰岛素受体被特定的小窝蛋白亚型结合和激活。此外，这些数据定义了小窝蛋白作为信号传导激活剂的新作用。
Recent data have demonstrated that caveolin, a major structural protein of caveolae, negatively regulates signaling molecules localized to caveolae, The interaction of caveolin with several caveolae-associated signaling proteins is mediated by the binding of the scaffolding region of caveolin to a hydrophobic amino acid-containing region within the regulated proteins. The presence of a similar motif within the insulin receptor kinase prompted us to investigate the caveolar localization and regulation of the insulin receptor by caveolin, We found that overexpression of caveolin-3 augmented insulin-stimulated phosphorylation of insulin receptor substrate-1 in 293T cells but not the phosphorylation of insulin receptor. Peptides corresponding to the scaffolding domain of caveolin potently stimulated insulin receptor kinase activity toward insulin receptor substrate-1 or a Src-derived peptide in vitro and in a caveolin subtype-dependent fashion. Peptides from caveolin-2 exhibited no effect, whereas caveolin-1 and -3 stimulated activity 10- and 17-fold, respectively. Peptides which increased insulin receptor kinase activity did so without affecting insulin receptor auto-phosphorylation. Furthermore, the insulin receptor bound to immobilized caveolin peptides, and this binding was inhibited in the presence of free caveolin-3 peptides. Thus, we have identified a novel mechanism by which the insulin receptor is bound and activated by specific caveolin subtypes, Furthermore, these data define a new role for caveolin as an activator of signaling.