연자: Michael J. Eck 교수 (Harvard Medical School & Dana-Farber Cancer Institute)
시간: 5월 11일 (월) 4시
연제: Structural and mechanistic approaches to understanding and overcoming drug resistance in EGFR-mutant lung cancer
장소: 하나과학관 A동 207호 (화상회의실)
초록: The cytosolic protein Mig6, encoded by the ERFFI1 gene, is a feedback inhibitor of EGFR family members that directly binds, inhibits and drives internalization of activated receptors. Here we find that EGFR is trapped upon phosphorylating Mig6 on Tyr394. This phosphorylation is primed by prior phosphorylation of an adjacent residue, Tyr395, by Src. A series of crystal structures of EGFR in complex with phosphorylated Mig6 fragments provide “snapshots” of the process, revealing the structural basis for binding and phosphorylation of the Src-primed substrate as well as a re-arrangement that leads to potent inhibition by the phosphorylated Y394/Y395 segment trapped in the substrate-binding cleft. Analysis of 1057 gliomas reveals frequent focal deletions of ERRFI, predominately in EGFR-amplified glioblastomas. Our findings mark Mig6 as a activity-based inhibitor of EGFR, explaining its specificity for active receptors, and show that loss of this previously unrecognized inhibitory mechanism is a driving event in cancer.