THE FUNCTION OF GRB2 IN LINKING THE INSULIN-RECEPTOR TO RAS SIGNALING PATHWAYS
THE FUNCTION OF GRB2 IN LINKING THE INSULIN-RECEPTOR TO RAS SIGNALING PATHWAYS
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DOI：
10.1126/science.8316835
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发表时间：
1993-06-25
期刊：
影响因子：
56.9
通讯作者：
SCHLESSINGER, J
中科院分区：
文献类型：
--
作者：
SKOLNIK, EY;BATZER, A;SCHLESSINGER, J
胰岛素诱导的细胞外信号调节激酶[ERK，也称为丝裂原活化蛋白（MAP）激酶]的活化由Ras介导。胰岛素主要通过增加鸟嘌呤核苷酸释放活性的速率来激活Ras。在这里，我们表明，胰岛素诱导的ERK激活增强稳定过表达的生长因子受体结合蛋白2（GRB 2），但不是过表达的GRB 2蛋白与点突变的Src同源2和3域。此外，显性负性形式的Ras（Ser 17被Asn取代）阻断了胰岛素诱导的过表达GRB 2的细胞中ERK的激活。GRB 2过表达导致鸟嘌呤核苷酸释放因子Sos（哺乳动物sons of sevenless基因同源物的产物）和GRB 2之间复合物的形成增加。在胰岛素刺激下，该复合物与酪氨酸磷酸化IRS-1（胰岛素受体底物-1）和Shc结合。与直接结合GRB 2-Sos复合物的活化的表皮生长因子受体相反，胰岛素受体的活化导致GRB 2-Sos与IRS-1和Shc相互作用，从而将胰岛素受体与Ras信号传导途径连接。
Insulin-induced activation of extracellular signal-regulated kinases [ERKs, also known as mitogen-activated protein (MAP) kinases] is mediated by Ras. Insulin activates Ras primarily by increasing the rate of guanine nucleotide-releasing activity. Here, we show that insulin-induced activation of ERKs was enhanced by stable overexpression of growth factor receptor-bound protein 2 (GRB2) but not by overexpression of GRB2 proteins with point mutations in the Src homology 2 and 3 domains. Moreover, a dominant negative form of Ras (with Ser17 substituted with Asn) blocked insulin-induced activation of ERKs in cells that overexpressed GRB2. GRB2 overexpression led to increased formation of a complex between the guanine nucleotide-releasing factor Sos (the product of the mammalian homolog of son of sevenless gene) and GRB2. In response to insulin stimulation, this complex bound to tyrosine-phosphorylated IRS-1 (insulin receptor substrate-1) and Shc. In contrast to the activated epidermal growth factor receptor that binds the GRB2-Sos complex directly, activation of the insulin receptor results in the interaction of GRB2-Sos with IRS-1 and Shc, thus linking the insulin receptor to Ras signaling pathways.