THE SH2 AND SH3 DOMAINS OF MAMMALIAN GRB2 COUPLE THE EGF RECEPTOR TO THE RAS ACTIVATOR MSOS1
THE SH2 AND SH3 DOMAINS OF MAMMALIAN GRB2 COUPLE THE EGF RECEPTOR TO THE RAS ACTIVATOR MSOS1
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DOI：
10.1038/363083a0
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发表时间：
1993-05-06
期刊：
影响因子：
64.8
通讯作者：
BOWTELL, D
中科院分区：
文献类型：
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作者：
ROZAKISADCOCK, M;FERNLEY, R;BOWTELL, D
许多酪氨酸激酶，包括表皮生长因子（EGF）、神经生长因子和胰岛素等激素受体，通过Ras蛋白1-4传递细胞内信号。与这些受体结合的配体刺激Ras鸟嘌呤-核苷酸交换活性5-9，并增加gtp结合的Ras10-12水平，表明这些酪氨酸激酶可能激活鸟嘌呤-核苷酸释放蛋白（GNRP）。在秀丽隐杆线虫和果蝇中，遗传学研究表明，酪氨酸激酶激活Ras需要蛋白Sem-5/drk，该蛋白包含单个Src-homology (SH) 2结构域和两个侧面的SH3结构域[13-15]。Sem-5与哺乳动物蛋白Grb2同源，Grb2通过其SH2结构域16-17结合自磷酸化的EGF受体和其他含磷酸酪氨酸的蛋白，如Shc。在啮齿动物成纤维细胞中，Grb2的SH3结构域与mSos1的富含脯氨酸的羧基末端尾部结合，mSos1是一种与果蝇Sos同源的蛋白。Sos是Ras信号传导18-20所必需的，包含一个与已知Ras- gnrps21 -23相关的中心结构域。EGF刺激诱导Grb2-mSos1复合物与自磷酸化的EGF受体结合，并导致mSos1磷酸化。因此，Grb2似乎将酪氨酸激酶与哺乳动物细胞中的Ras-GNRP联系起来。
MANY tyrosine kinases, including the receptors for hormones such as epidermal growth factor (EGF), nerve growth factor and insulin, transmit intracellular signals through Ras proteins1-4. Ligand binding to such receptors stimulates Ras guanine-nucleotide-exchange activity5-9 and increases the level of GTP-bound Ras10-12, suggesting that these tyrosine kinases may activate a guanine-nucleotide releasing protein (GNRP). In Caenorhabditis elegans and Drosophila, genetic studies have shown that Ras activation by tyrosine kinases requires the protein Sem-5/drk, which contains a single Src-homology (SH) 2 domain and two flanking SH3 domains13-15. Sem-5 is homologous to the mammallian protein Grb2, which binds the autophosphorylated EGF receptor and other phosphotyrosine-containing proteins such as Shc through its SH2 domain16-17. Here we show that in rodent fibroblasts, the SH3 domains of Grb2 are bound to the proline-rich carboxy-terminal tail of mSos1, a protein homologous to Drosophila Sos. Sos is required for Ras signalling18-20 and contains a central domain related to known Ras-GNRPs21-23. EGF stimulation induces binding of the Grb2-mSos1 complex to the autophosphorylated EGF receptor, and mSos1 phosphorylation. Grb2 therefore appears to link tyrosine kinases to a Ras-GNRP in mammalian cells.