Regulation of EGF receptor dynamics by protein tyrosine phosphatases

摘要: The phosphorylated epidermal growth factor receptor (EGFR) initiates intracellular signaling processes that regulate cell growth, survival, and migration, disregulated EGFR-mediated occurs in many cancers. While the lead to EGFR activation phosphorylation have been studied detail, quantitative aspects of spatiotemporal regulation by protein tyrosines phosphatases (PTPs) are not well understood. To begin address this, we developed a new compartmentalized mechanistic model dynamics used it interpret biochemical measurements show is dephosphorylated at plasma membrane interior with time scale small compared scales for internalization. By expanding our computational experimental data set, went on demonstrate dephosphorylation surprisingly does affect phosphorylation-dependent internalization because separation phospho-dependent enables enter clathrin-coated pits prior being acted upon PTPs. This same does, however, allow PTPs control association adapter proteins downstream signaling. Thus, provides understanding how participates number simultaneous compete C-terminal phosphotyrosines. We apply this developing predictive models understand such might differentially impact efficacy antibodies kinase inhibitors targeting EGFR. also quantitatively predict kinetics as rapid found initiated tyrosine kinases dimerize structurally distinct ways observed naturally among family (RTKs). Ultimately, thesis significantly refines signaling, additional testable predictions related fundamental complex nucleation EGFR-targeted therapeutics, offers basic framework exploring other