Epidermal growth factor receptor translocation to the mitochondria: regulation and effect.
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.
Demory
Michelle L
ML
Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908.
Boerner
Julie L
JL
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.
Davidson
Robert
R
Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908.
Faust
William
W
Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908.
Miyake
Tsuyoshi
T
Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908.
Lee
Icksoo
I
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201.
Hüttemann
Maik
M
Karmanos Cancer Institute, Wayne State University, Detroit, Michigan 48201; Center for Molecular Medicine and Genetics, Wayne State University, Detroit, Michigan 48201.
Douglas
Robert
R
Department of Pediatrics, University of California, San Diego, La Jolla, California 92093.
Haddad
Gabriel
G
Department of Pediatrics, University of California, San Diego, La Jolla, California 92093; Department of Neuroscience, University of California, San Diego, La Jolla, California 92093.
Parsons
Sarah J
SJ
Department of Microbiology and the Cancer Center, University of Virginia, Charlottesville, Virginia 22908. Electronic address: sap@virginia.edu.
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D045744:Cell Line, Tumor; D003576:Electron Transport Complex IV / Q000235:genetics / Q000378:metabolism*; D004815:Epidermal Growth Factor / Q000235:genetics / Q000378:metabolism*; D066246:ErbB Receptors / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D008928:Mitochondria / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D011505:Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism*; D019061:src-Family Kinases
D011518:Proto-Oncogene Proteins; D004815:Epidermal Growth Factor; D003576:Electron Transport Complex IV; C512478:EGFR protein, human; D066246:ErbB Receptors; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; C000631346:CSK protein, human