Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism

Yan Ding, Zixing Liu, Shruti Desai, Yuhua Zhao, Hao Liu, Lewis K. Pannell, Hong Yi, Elizabeth R. Wright, Laurie B. Owen, Windy Dean-Colomb, Oystein Fodstad, Jianrong Lu, Susan P. LeDoux, Glenn L. Wilson and Ming Tan ()
Additional contact information
Yan Ding: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Zixing Liu: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Shruti Desai: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Yuhua Zhao: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Hao Liu: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Lewis K. Pannell: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Hong Yi: Robert P. Apkarian Integrated Electron Microscopy Core, College of Medicine, Emory University
Elizabeth R. Wright: Robert P. Apkarian Integrated Electron Microscopy Core, College of Medicine, Emory University
Laurie B. Owen: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Windy Dean-Colomb: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
Oystein Fodstad: Institute for Cancer Research, The Norwegian Radium Hospital
Jianrong Lu: University of Florida
Susan P. LeDoux: College of Medicine, University of South Alabama
Glenn L. Wilson: College of Medicine, University of South Alabama
Ming Tan: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue

Nature Communications, 2012, vol. 3, issue 1, 1-12

Abstract: Abstract It is well known that ErbB2, a receptor tyrosine kinase, localizes to the plasma membrane. Here we describe a novel observation that ErbB2 also localizes in mitochondria of cancer cells and patient samples. We found that ErbB2 translocates into mitochondria through association with mtHSP70. Additionally, mitochondrial ErbB2 (mtErbB2) negatively regulates mitochondrial respiratory functions. Oxygen consumption and activities of complexes of the mitochondrial electron transport chain were decreased in mtErbB2-overexpressing cells. Mitochondrial membrane potential and cellular ATP levels were also decreased. In contrast, mtErbB2 enhanced cellular glycolysis. The translocation of ErbB2 and its impact on mitochondrial function are kinase dependent. Interestingly, cancer cells with higher levels of mtErbB2 were more resistant to the ErbB2-targeting antibody trastuzumab. Our study provides a novel perspective on the metabolic regulatory function of ErbB2 and reveals that mtErbB2 has an important role in the regulation of cellular metabolism and cancer cell resistance to therapeutics.

Date: 2012
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DOI: 10.1038/ncomms2236

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