EGFR exhibits biased signaling, whereby growth factor or mutation-dependent changes in receptor conformation and/or dynamics elicit distinct intracellular outcomes. We find 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.

Coiled coil control of diverse EGFR functions

ACS Spring Meeting 2021

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