Eunyoung Park1,2,11, Nayoung Kim3,4,11, Scott B Ficarro1,5, Yi Zhang1,5, Byung Il Lee1,6, Ahye Cho3,4, Kihong Kim4, Angela K J Park3,4, Woong-Yang Park3,4, Bradley Murray7, Matthew Meyerson7-9, Rameen Beroukhim1,7,8,10, Jarrod A Marto1,2,5, Jeonghee Cho3,4,* & Michael J Eck1,2,*
1Department of Cancer Biology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 2Department of Biological Chemistry and Molecular Pharmacology, Harvard Medical School, Boston, Massachusetts, USA. 3Samsung Genome Institute, Samsung Medical Center, Seoul, Republic of Korea. 4Samsung Advanced Institute for Health Sciences and Technology, SungKyunKwan University, Seoul, Republic of Korea. 5Blais Proteomics Center, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 6Biomolecular Function Research Branch, Division of Convergence Technology, Research Institute, National Cancer Center, Goyang, Republic of Korea. 7Broad Institute of Harvard and MIT, Cambridge, Massachusetts, USA. 8Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts, USA. 9Department of Pathology, Harvard Medical School, Boston, Massachusetts, USA. 10Department of Medicine, Harvard Medical School, Boston, Massachusetts, USA. 11These authors contributed equally to this work
*Correspondence to : Michael J Eck or Jeonghee Cho
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.