Moving to the Mitochondria

Abstract

Epidermal growth factor receptor (EGFR) and nonreceptor tyrosine kinase c-Src, whose combined overexpression occurs in some breast cancers, cooperate to promote transformed characteristics when overexpressed in fibroblasts. Their synergistic interaction, which depends on c-Src phosphorylation of EGFR tyrosine 845 (pY845), is independent of EGFR kinase activity and of its activation of the mitogen-associated protein kinase signaling pathway. Boerner et al. screened a phage display library with a peptide corresponding to the region of EGFR that contains pY845 and identified cytochrome c oxidase subunit II (CoxII) as a binding partner. In mouse fibroblasts overexpressing EGFR and c-Src and in a breast cancer cell line that overexpresses both EGFR and c-Src, CoxII coimmunoprecipitated with EGFR. Coimmunoprecipitation, which was enhanced by EGF treatment, did not occur with overexpression of a catalytically inactive c-Src mutant or when Y845 was replaced by phenylalanine (Y845F-EGFR). The authors used confocal microscopy and biochemical fractionation to show that EGF stimulated translocation of EGFR to the mitochondria. Mutational analysis indicated that this translocation depended on EGFR kinase activity but not on Y845 phosphorylation. Confocal microscopy indicated that EGFR and CoxII colocalized in mitochondria and EGFR and CoxII coimmunoprecipitated from a mitochondrial fraction of a breast cancer cell line that overexpresses EGFR and c-Src (MDA-MB-231). When Y845F-EGFR was expressed in MDA-MB-231, cells became more sensitive to apoptosis in response to serum withdrawal, and the ability of EGF to protect cells from apoptosis induced by treatment with the antineoplastic drug adriamycin was attenuated. Thus, the authors suggest that the ability of EGFR to translocate to mitochondria and to bind to CoxII may contribute to the synergistic effects of c-Src and EGFR on oncogenesis. J. L. Boerner, M. L. Demory, C. Silva, S. J. Parsons, Phosphorylation of Y845 on the epidermal growth factor receptor mediates binding to the mitochondrial protein cytochrome oxidase subunit II. Mol. Cell. Biol . 24 , 7059-7071 (2004). [Abstract] [Full Text]