Simulation of the regulation of EGFR endocytosis and EGFR-ERK signaling by endophilin-mediated RhoA-EGFR crosstalk

Abstract

Deregulations of EGFR endocytosis in EGFR-ERK signaling are known to cause cancers and developmental disorders. Mutations that impaired c-Cbl-EGFR association delay EGFR endocytosis and produce higher mitogenic signals in lung cancer. ROCK, an effector of small GTPase RhoA was shown to negatively regulate EGFR endocytosis via endophilin A1. A mathematical model was developed to study how RhoA and ROCK regulate EGFR endocytosis. Our study suggested that over-expressing RhoA as well as ROCK prolonged ERK activation partly by reducing EGFR endocytosis. Overall, our study hypothesized an alternative role of RhoA in tumorigenesis in addition to its regulation of cytoskeleton and cell motility.