Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism
Open Access
- 1 January 2012
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Communications
- Vol. 3 (1), 1-12
- https://doi.org/10.1038/ncomms2236
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.Keywords
This publication has 41 references indexed in Scilit:
- Overcoming Trastuzumab Resistance in Breast Cancer by Targeting Dysregulated Glucose MetabolismCancer Research, 2011
- Phosphate-induced Apoptosis of Hypertrophic Chondrocytes Is Associated with a Decrease in Mitochondrial Membrane Potential and Is Dependent upon Erk1/2 PhosphorylationJournal of Biological Chemistry, 2010
- Cell Signaling by Receptor Tyrosine KinasesCell, 2010
- Warburg effect in chemosensitivity: Targeting lactate dehydrogenase-A re-sensitizes Taxol-resistant cancer cells to TaxolMolecular Cancer, 2010
- Understanding the Warburg Effect: The Metabolic Requirements of Cell ProliferationScience, 2009
- Glucose metabolism inhibits apoptosis in neurons and cancer cells by redox inactivation of cytochrome cNature, 2008
- Localization of PTP-1B, SHP-2, and Src Exclusively in Rat Brain Mitochondria and Functional ConsequencesJournal of Biological Chemistry, 2008
- Cancer Cell Metabolism: Warburg and BeyondCell, 2008
- Survival of Cancer Cells Is Maintained by EGFR Independent of Its Kinase ActivityCancer Cell, 2008
- ErbB receptors: from oncogenes to targeted cancer therapiesJCI Insight, 2007