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Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias
Author(s) -
Chun Hu,
C.A. Leche,
Anatoly Kiyatkin,
Zhaolong Yu,
Steven E. Stayrook,
Kathryn M. Ferguson,
Mark A. Lemmon
Publication year - 2022
Publication title -
nature
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 15.993
H-Index - 1226
eISSN - 1476-4687
pISSN - 0028-0836
DOI - 10.1038/s41586-021-04393-3
Subject(s) - epiregulin , epidermal growth factor receptor , epidermal growth factor , extracellular , tyrosine kinase , mutation , cancer research , chemistry , biology , signal transduction , microbiology and biotechnology , receptor , biochemistry , gene , amphiregulin
The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer 1,2 , and is an important therapeutic target. EGFR inhibitors have been successful in lung cancer, where mutations in the intracellular tyrosine kinase domain activate the receptor 1 , but not in glioblastoma multiforme (GBM) 3 , where mutations occur exclusively in the extracellular region. Here we show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands 4 . Different growth factor ligands stabilize distinct EGFR dimer structures 5 that signal with different kinetics to specify or bias outcome 5,6 . EGF itself induces strong symmetric dimers that signal transiently to promote proliferation. Epiregulin (EREG) induces much weaker asymmetric dimers that drive sustained signalling and differentiation 5 . GBM mutations reduce the ability of EGFR to distinguish EREG from EGF in cellular assays, and allow EGFR to form strong (EGF-like) dimers in response to EREG and other low-affinity ligands. Using X-ray crystallography, we further show that the R84K GBM mutation symmetrizes EREG-driven extracellular dimers so that they resemble dimers normally seen with EGF. By contrast, a second GBM mutation, A265V, remodels key dimerization contacts to strengthen asymmetric EREG-driven dimers. Our results argue for an important role of altered ligand discrimination by EGFR in GBM, with potential implications for therapeutic targeting.

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