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Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism

Author

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  • Yan Ding

    (Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue
    Present address: Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010, USA)

  • 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
    College of Medicine, University of South Alabama)

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.

Suggested Citation

  • 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 & , 2012. "Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism," Nature Communications, Nature, vol. 3(1), pages 1-12, January.
    • Handle: RePEc:nat:natcom:v:3:y:2012:i:1:d:10.1038_ncomms2236
    DOI: 10.1038/ncomms2236
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