Epidermal growth factor receptor localization at the mitochondria: regulation and effect

Co-overexpression of EGFR and c-Src frequently occurs in human tumors, and this co-overexpression is linked to enhanced tumor growth. In experimental systems, this synergistic growth requires EGF-dependent association of c-Src with the EGFR and phosphorylation of tyrosine 845 (pY845) of the receptor by c-Src. Expression of a mutant EGFR with a phenylalanine substitution at position Y845 (Y845F) abrogates the increases in DNA synthesis observed in wild type EGFR expressing cells, suggesting that pY845 elicits a strong mitogenic signal. Y845F mutant EGFR retains kinase activity, and continues to phosphorylate both Shc and MAPK, following EGF stimulation, suggesting that the pY845 mitogenic signal is independent of classical mediators of EGFR signaling. In an effort to identify possible effectors of the pY845 mitogenic signal, phage display screening was undertaken. Five of twenty independent clones that bound to a pY845 peptide encoded fragments of the mitochondrial encoded and localized protein, cytochrome c oxidase subunit II (CoxII). The association between EGFR and CoxII was verified in Cos7 cells, and wt, but not Y845F EGFR was found to protect cells from adriamycin-induced apoptosis in MDA-MB-231 breast cancer cells. But, these results led to many questions. The first question was where could these two proteins associate with one another? This dissertation describes results suggesting that EGFR can transiently translocate to the mitochondria in an EGF-inducible manner and shows that EGFR and CoxII can associate in this organelle. The unexpected finding of mitochondrial-localized EGFR led to further questions of possible regulators of this novel translocation process. c-Src translocation to the mitochondria was also found to occur, and with the same kinetics as the EGFR. Overexpression and catalytic activity of EGFR iii and c-Src as well as clathrin-mediated endocytosis and a mitochondrial localization signal affected EGFR mitochondrial localization. The final question addressed in this dissertation was what were the possible effects of EGFR-mitochondrial localization? Results show that EGFR and c-Src were capable of phosphorylating CoxII and EGF stimulation altered mitochondrial function. Combined, these findings suggest that EGFR may play a novel role in enhancing cellular growth and survival via its mitochondria localization-induced association with, and modification of, CoxII.

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