Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908.
Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908; Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Department of Pharmacology, Wayne State University, Detroit, Michigan 48201.
J Biol Chem. 2009 Dec 25;284(52):36592-36604. doi: 10.1074/jbc.M109.000760. Epub 2009 Oct 19.
Co-overexpression of the epidermal growth factor (EGF) receptor (EGFR) and c-Src frequently occurs in human tumors and 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 Tyr-845 of the receptor by c-Src. A search for signaling mediators of Tyr(P)-845 revealed that mitochondrial cytochrome c oxidase subunit II (CoxII) binds EGFR in a Tyr(P)-845- and EGF-dependent manner. In cells this association involves translocation of EGFR to the mitochondria, but regulation of this process is ill-defined. The current study demonstrates that c-Src translocates to the mitochondria with similar kinetics as EGFR and that the catalytic activity of EGFR and c-Src as well as endocytosis and a mitochondrial localization signal are required for these events. CoxII can be phosphorylated by EGFR and c-Src, and EGF stimulation reduces Cox activity and cellular ATP, an event that is dependent in large part on EGFR localized to the mitochondria. These findings suggest EGFR plays a novel role in modulating mitochondrial function via its association with, and modification of CoxII.
表皮生长因子受体 (EGFR) 和 c-Src 的共过表达在人类肿瘤中经常发生，并与增强的肿瘤生长有关。在实验系统中，这种协同生长需要 EGFR 与 c-Src 的 EGF 依赖性结合，以及 c-Src 对受体 Tyr-845 的磷酸化。对 Tyr(P)-845 的信号转导介质的搜索表明，线粒体细胞色素 c 氧化酶亚基 II (CoxII) 以 Tyr(P)-845 和 EGF 依赖性的方式与 EGFR 结合。在细胞中，这种结合涉及 EGFR 向线粒体的易位，但该过程的调节尚不清楚。本研究表明，c-Src 以与 EGFR 相似的动力学向线粒体易位，并且 EGFR 和 c-Src 的催化活性、内吞作用和线粒体定位信号对于这些事件是必需的。CoxII 可被 EGFR 和 c-Src 磷酸化，EGF 刺激可降低 Cox 活性和细胞内 ATP，这一事件在很大程度上依赖于位于线粒体的 EGFR。这些发现表明，EGFR 通过与 CoxII 的结合及其修饰，在调节线粒体功能方面发挥了新的作用。
