Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.

Nat Struct Mol Biol
Authors
Keywords
Abstract

Mig6 is a feedback inhibitor that directly binds, inhibits and drives internalization of ErbB-family receptors. Mig6 selectively targets activated receptors. Here we found that the epidermal growth factor receptor (EGFR) phosphorylates Mig6 on Y394 and that this phosphorylation is primed by prior phosphorylation of an adjacent residue, Y395, 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 that can be modulated by Src. Loss of Mig6 is a driving event in human cancer; analysis of 1,057 gliomas reveals frequent focal deletions of ERRFI1, the gene that encodes Mig6, in EGFR-amplified glioblastomas.

Year of Publication
2015
Journal
Nat Struct Mol Biol
Volume
22
Issue
9
Pages
703-11
Date Published
2015 Sep
ISSN
1545-9985
URL
DOI
10.1038/nsmb.3074
PubMed ID
26280531
PubMed Central ID
PMC4790445
Links
Grant list
R01 CA116020 / CA / NCI NIH HHS / United States
CA154303 / CA / NCI NIH HHS / United States
CA116020 / CA / NCI NIH HHS / United States
CA178860 / CA / NCI NIH HHS / United States
CA156021 / CA / NCI NIH HHS / United States