Abstract 1202: A role for adhesion in epidermal growth factor receptor (EGFR)-mitochondrial translocation

Abstract

Abstract Co-overexpression of the epidermal growth factor (EGF) receptor (EGFR) and c-Src often occurs in tumors, resulting in synergistic increases in oncogenic activity and correlation with poor patient prognosis in several cancers1. We have demonstrated that overexpression of EGFR and c-Src, and stimulation with EGF results in the transient translocation of both kinases to the mitochondria, which correlates with reduced adriamycin-induced apoptosis, and lowered O2 consumption and ATP production. Translocation requires EGFR endocytosis, as well as EGFR and c-Src catalytic activity2,3. It has been suggested that to translocate to the mitochondria, EGFR is retrograde trafficked to the ER, where it is removed from the membrane and then enters the mitochondria4. Here we show that EGFR remains associated with endosomal membranes upon translocation from the plasma membrane to mitochondria, as demonstrated by the colocalizaton of EGFR, mitochondria and extracellularly applied dextran. This translocation requires the activity of integrins, as cells plated on poly-L-lysine show significantly reduced mitochondrial-EGFR in response to EGF stimulation. Alternatively, adhesion to fibronectin in the absence of other extracellular signals was sufficient to activate EGFR and cause mitochondrial translocation. Adhesion resulted in phosphorylation on Y845, Y992, and Y1068, but not Y1045 of EGFR, while EGF stimulation, even on poly-L-lysine, resulted in the phosphorylation of all these sites. pY1045 is involved in Cbl recruitment and lysosomal degradation of EGFR5, suggesting adhesion stimulates EGFR signaling and mitochondrial translocation, while preventing lysosomal degradation. Future work will examine the role of Y1045 in mitochondrial EGFR translocation, mitochondrial function and resistance to chemotherapy.