Nuclear existence of epidermal growth factor receptor (EGFR) has been documented for more than a decade. However, our understanding of the physiological contribution of the nuclear EGFR signaling to the biology in cancer cells is just about to emerge. In regenerating liver, increased nuclear EGFR expression is closely associated with active hepatocyte proliferation. In cancer, nuclear expression of EGFR is frequently associated with multiple tumor types, including breast cancer, and has been shown to be a poor prognosis tumor marker for cancer patients. We recently demonstrated that the proliferating cell nuclear antigen (PCNA) protein is subject to tyrosine phosphorylation at tyrosine 211 (Tyr 211) by nuclear EGFR and the phosphorylation enhances PCNA stability. In addition, EGFR appears to form functional complexes with multiple nuclear proteins. In this proposal, we aim to characterize the interactome of nuclear EGFR and identify its novel nuclear partners (Aim1). Furthermore, we will extend our study to explore the importance of the nuclear EGFR mediated Tyr 211 phosphorylation of PCNA in cancer cell proliferation (Aim2). Finally, we will study the nuclear EGFR for its post-translational modification in particular tyrosine phosphorylation, and the associated functions in the nucleus (Aim3). The proposed work will greatly extend our knowledge on the nuclear function of EGFR, which may facilitate the future success to develop novel therapies that target the nuclear EGFR signaling pathway in cancer.
