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Glioblastoma mutations alter EGFR dimer structure to prevent ligand bias. | LitMetric

AI Article Synopsis

Article Abstract

The epidermal growth factor receptor (EGFR) is frequently mutated in human cancer, 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, but not in glioblastoma multiforme (GBM), where mutations occur exclusively in the extracellular region. Here we show that common extracellular GBM mutations prevent EGFR from discriminating between its activating ligands. Different growth factor ligands stabilize distinct EGFR dimer structures that signal with different kinetics to specify or bias outcome. 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. 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8857055PMC
http://dx.doi.org/10.1038/s41586-021-04393-3DOI Listing

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