Structure and mechanism of activity-based inhibition of the EGF receptor by Mig6.
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.
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA USA.
Eunyoung
E
Park
Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea.
Nayoung
N
Kim
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA USA.
Scott B
SB
Ficarro
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA USA.
Yi
Y
Zhang
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.|Biomolecular Function Research Branch, Division of Convergence Technology, Research Institute, National Cancer Center, Goyang, Gyeonggi Republic of Korea.
Byung Il
BI
Lee
Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea.
Ahye
A
Cho
Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea.
Kihong
K
Kim
Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea.
Angela K J
AKJ
Park
Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea.
Woong-Yang
WY
Park
Broad Institute of Harvard and MIT, Cambridge, MA USA.
Bradley
B
Murray
Broad Institute of Harvard and MIT, Cambridge, MA USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA.|Department of Pathology, Harvard Medical School, Boston, MA USA.
Matthew
M
Meyerson
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.|Broad Institute of Harvard and MIT, Cambridge, MA USA.|Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA USA.|Department of Medicine, Harvard Medical School, Boston, MA USA.
Rameen
R
Beroukhim
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA USA.|Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, MA USA.
Jarrod A
JA
Marto
Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea.|Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea.
Jeonghee
J
Cho
Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, MA USA.|Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, MA USA.
Michael J
MJ
Eck
D048868:Adaptor Proteins, Signal Transducing / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D018360:Crystallography, X-Ray; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D017353:Gene Deletion; D005910:Glioma / Q000473:pathology; D006801:Humans; D008958:Models, Molecular; D010766:Phosphorylation; D011485:Protein Binding; D011487:Protein Conformation; D011499:Protein Processing, Post-Translational; D025521:Tumor Suppressor Proteins / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; C484017:ERRFI1 protein, human; D025521:Tumor Suppressor Proteins; D066246:ErbB Receptors; D019061:src-Family Kinases