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Nat Struct Mol Biol. 2015 Sep;22(9):703-711. doi: 10.1038/nsmb.3074. Epub 2015 Aug 17.

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

Park E#1,2, Kim N#3,4, Ficarro SB1,5, Zhang Y1,5, Lee BI1,6, Cho A3,4, Kim K4, Park AKJ3,4, Park WY3,4, Murray B7, Meyerson M7,8,9, Beroukhim R1,7,8,10, Marto JA1,2,5, Cho J3,4, Eck MJ1,2.

Author information

1
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.
2
Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA USA.
3
Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.
4
Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea.
5
Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA USA.
6
Biomolecular Function Research Branch, Division of Convergence Technology, Research Institute, National Cancer Center, Goyang, Gyeonggi Republic of Korea.
7
Broad Institute of Harvard and MIT, Cambridge, MA USA.
8
Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA.
9
Department of Pathology, Harvard Medical School, Boston, MA USA.
10
Department of Medicine, Harvard Medical School, Boston, MA USA.
#
Contributed equally

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.

PMID:
26280531
PMCID:
PMC4790445
DOI:
10.1038/nsmb.3074
[Indexed for MEDLINE]
Free PMC Article

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