title: Receptor tyrosine kinase ErbB2 translocates into mitochondria and regulates cellular metabolism.
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.
authors.affiliation: Mitchell Cancer Institute, University of South Alabama, MCI 3016, 1600 Spring Hill Avenue, Mobile, Alabama 36604, USA.
authors.forename: Yan
authors.initials: Y
authors.lastname: Ding
authors.forename: Zixing
authors.initials: Z
authors.lastname: Liu
authors.forename: Shruti
authors.initials: S
authors.lastname: Desai
authors.forename: Yuhua
authors.initials: Y
authors.lastname: Zhao
authors.forename: Hao
authors.initials: H
authors.lastname: Liu
authors.forename: Lewis K
authors.initials: LK
authors.lastname: Pannell
authors.forename: Hong
authors.initials: H
authors.lastname: Yi
authors.forename: Elizabeth R
authors.initials: ER
authors.lastname: Wright
authors.forename: Laurie B
authors.initials: LB
authors.lastname: Owen
authors.forename: Windy
authors.initials: W
authors.lastname: Dean-Colomb
authors.forename: Oystein
authors.initials: O
authors.lastname: Fodstad
authors.forename: Jianrong
authors.initials: J
authors.lastname: Lu
authors.forename: Susan P
authors.initials: SP
authors.lastname: LeDoux
authors.forename: Glenn L
authors.initials: GL
authors.lastname: Wilson
authors.forename: Ming
authors.initials: M
authors.lastname: Tan
mesh_terms: D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology; D001943:Breast Neoplasms / Q000378:metabolism / Q000503:physiopathology; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000502:physiology; D019008:Drug Resistance, Neoplasm / Q000502:physiology; D004579:Electron Transport / Q000502:physiology; D005260:Female; D006019:Glycolysis / Q000502:physiology; D018840:HSP70 Heat-Shock Proteins / Q000502:physiology; D006801:Humans; D008928:Mitochondria / Q000378:metabolism / Q000502:physiology*; D010085:Oxidative Phosphorylation; D021381:Protein Transport; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism / Q000502:physiology*; D000068878:Trastuzumab
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D018840:HSP70 Heat-Shock Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human