Skolnik E Y, Batzer A, Li N, Lee C H, Lowenstein E, Mohammadi M, Margolis B, Schlessinger J
Department of Pharmacology, New York University Medical Center, NY 10016.
Science. 1993 Jun 25;260(5116):1953-5. doi: 10.1126/science.8316835.
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.
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]的激活由Ras介导。胰岛素主要通过提高鸟嘌呤核苷酸释放活性的速率来激活Ras。在此，我们表明，生长因子受体结合蛋白2（GRB2）的稳定过表达增强了胰岛素诱导的ERK激活，但Src同源2和3结构域中具有点突变的GRB2蛋白的过表达则没有这种作用。此外，一种显性负性形式的Ras（Ser17被Asn取代）在过表达GRB2的细胞中阻断了胰岛素诱导的ERK激活。GRB2过表达导致鸟嘌呤核苷酸释放因子Sos（七号染色体失活基因哺乳动物同源物的产物）与GRB2之间形成的复合物增加。响应胰岛素刺激，该复合物与酪氨酸磷酸化的胰岛素受体底物-1（IRS-1）和Shc结合。与直接结合GRB2-Sos复合物的活化表皮生长因子受体不同，胰岛素受体的激活导致GRB2-Sos与IRS-1和Shc相互作用，从而将胰岛素受体与Ras信号通路联系起来。
