Regulation of epidermal growth factor receptor endocytosis

Epidermal growth factor receptor (EGFR) and its signaling pathways have profound effects on various important cellular processes. Deregulated EGFR signaling is implicated in the development of many diseases like cancer. As a self-defense mechanism, ligand-induced EGFR endocytosis functions to terminate EGFR signaling and thus maintain cellular homeostasis. In this thesis, I studied the regulation of EGFR endocytosis from three aspects.;Most studies regarding the role of the EGFR C-terminal domain in EGFR internalization are done in the context of EGFR kinase activation. I next studied the role of EGFR C-terminus in EGF-induced EGFR internalization with or without EGFR kinase activation. We showed that EGFR C-terminal sequence 1005-1017 and 1010LL di-leucine motif are essential for EGFR internalization independent of EGFR kinase activation and autophosphorylation.;Last I studied the possible mechanism for dimerization-mediated EGFR internalization. By utilizing a controlled dimerization system whereby EGFR and other ErbB family receptors can be specifically homodimerized or heterodimerized, I was able to show that a pair of identical internalization signals is required for EGFR endocytosis. Based on our data, we propose a "dimerization" model to describe the regulation of EGF-induced EGFR endocytosis.;In summary, the findings herein presented provide the evidence suggesting that EGF-induced EGFR internalization is controlled by receptor dimerization rather than receptor kinase activation, and therefore represent a significant advance in the understanding of the regulatory mechanisms of EGFR endocytosis.;Given that ligand binding is essential for the rapid internalization of EGFR, the events induced by ligand binding, including receptor dimerization, activation of intrinsic tyrosine kinase and autophosphorylation, most likely contribute to the regulation of ligand-induced EGFR internalization. I therefore first examined the critical event that controls EGFR endocytosis. We showed that rather than kinase activation, proper EGFR dimerization is necessary and sufficient to stimulate EGFR internalization. Our results also define a new role for EGFR dimerization: by itself it can drive EGFR internalization, independent of its role in the activation of EGFR kinase.