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Coiled coil control of diverse EGFR functions
Author(s) -
Mozumdar Deepto,
Quach Kim,
Doerner Amy,
Schepartz Alanna
Publication year - 2021
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2021.35.s1.03155
Subject(s) - autophosphorylation , endocytic cycle , microbiology and biotechnology , intracellular , epidermal growth factor receptor , tyrosine kinase , kinase , phosphorylation , biology , coiled coil , signal transduction , chemistry , protein kinase a , receptor , biochemistry , endocytosis
EGFR exhibits biased signaling, whereby growth factor or mutation‐dependent changes in receptor conformation and/or dynamics elicit distinct intracellular outcomes. We report that many intracellular EGFR outcomes are controlled by a two‐state coiled coil switch located within the juxtamembrane segment (JM), an essential component of the cytosolic dimer interface. The position of this switch defines the path of endocytic trafficking, the extent and dynamics of autophosphorylation, c‐Cbl recruitment, and ubiquitination, and whether or not EGFR is degraded within lysosomes. It also predicts kinase‐independent effects of oncogenic mutations and clinically relevant tyrosine kinase inhibitors (TKIs) that promote lysosome‐based degradation. These findings provide a model for biased EGFR signaling, insights into kinase‐independent activities of EGFR and clinically relevant TKIs, and identify new strategies for modulating protein lifetime (1). (1) Mozumdar, D., Quach, K., Doerner, A.E. & Schepartz, A. Coiled coil control of diverse EGFR functions, b ioRxiv : https://doi.org/10.1101/2020.12.10.419739