Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.
Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.
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DOI：
10.1038/nsmb.3074
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发表时间：
2015-09
影响因子：
16.8
通讯作者：
Eck MJ
中科院分区：
文献类型：
--
作者：
Park E;Kim N;Ficarro SB;Zhang Y;Lee BI;Cho A;Kim K;Park AKJ;Park WY;Murray B;Meyerson M;Beroukhim R;Marto JA;Cho J;Eck MJ
Mig 6是直接结合、抑制和驱动ErbB家族受体内化的反馈抑制剂。Mig 6选择性靶向激活的受体。在这里，我们发现，EGF受体磷酸化Mig 6的Tyr 394，这种磷酸化是由一个相邻的残基，Tyr 395，由Src事先磷酸化引发。人EGFR-Mig 6复合物的晶体结构揭示了引发的Mig 6磷酸化增强的结构基础，并显示了Mig 6在EGFR磷酸化后如何重排，以有效地不可逆地抑制催化其磷酸化的相同受体。这种双重磷酸化位点允许Mig 6以需要靶受体活化的方式抑制EGFR，并且可以通过Src进行调节。Mig 6的缺失是人类癌症的驱动事件;对1057例胶质瘤的分析显示，EGFR扩增的胶质母细胞瘤中编码Mig 6的基因ERRFI经常发生局灶性缺失。
Mig6 is a feedback inhibitor that directly binds, inhibits and drives internalization of ErbB-family receptors. Mig6 selectivity targets activated receptors. Here we find that the EGF receptor phosphorylates Mig6 on Tyr394, and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Tyr395, by Src. Crystal structures of human EGFR–Mig6 complexes reveal the structural basis for enhanced phosphorylation of primed Mig6 and show how Mig6 rearranges after phosphorylation by EGFR to effectively irreversibly inhibit the same receptor that catalyzed its phosphorylation. This dual phosphorylation site allows Mig6 to inactivate EGFR in a manner that requires activation of the target receptor and can be modulated by Src. Loss of Mig6 is a driving event in human cancer; analysis of 1057 gliomas reveals frequent focal deletions of ERRFI, the gene that encodes Mig6, in EGFR-amplified glioblastomas.