EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src.
EGF-receptor specificity for phosphotyrosine-primed substrates provides signal integration with Src.
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DOI：
10.1038/nsmb.3117
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发表时间：
2015-12
影响因子：
16.8
通讯作者：
Cantley LC
中科院分区：
文献类型：
--
作者：
Begley MJ;Yun CH;Gewinner CA;Asara JM;Johnson JL;Coyle AJ;Eck MJ;Apostolou I;Cantley LC
表皮生长因子受体(EGFR)的异常激活通过激活Ras-MAPK和其他途径参与了许多人类癌症的发生。Src家族的蛋白激酶可增强EGFR信号转导，但其机制尚不清楚。在这里，我们表明，人的EGFR优先磷酸化由先前的磷酸化启动的多肽底物。利用基于适配蛋白Shc1序列的多肽，我们证明了Src介导了启动磷酸化，促进了EGFR随后的磷酸化。重要的是，双磷酸化的Shc1肽与RAS激活剂Grb2结合得更紧密，Grb2是激活RAS-MAPK途径的关键步骤，而不是单一的磷酸化肽。最后，EGFR与启动的Shc1肽形成的复合体的晶体结构揭示了EGFR底物特异性的结构基础。这些结果为Src和EGFR信号与下游效应因子如RAS的整合提供了分子解释。
Aberrant activation of the EGF receptor (EGFR) contributes to many human cancers by activating the Ras-MAPK and other pathways. EGFR signaling is augmented by Src-family kinases, but the mechanism is poorly understood. Here, we show that human EGFR preferentially phosphorylates peptide substrates that are primed by a prior phosphorylation. Utilizing peptides based on the sequence of the adaptor protein Shc1, we show that Src mediates the priming phosphorylation, promoting subsequent phosphorylation by EGFR. Importantly, the doubly phosphorylated Shc1 peptide binds more tightly to the Ras activator Grb2, a key step in activating the Ras-MAPK pathway, than singly phosphorylated peptides. Finally, a crystal structure of EGFR in complex with a primed Shc1 peptide reveals the structural basis for EGFR substrate specificity. These results provide a molecular explanation for the integration of Src and EGFR signaling with downstream effectors such as Ras.