title: The growth factor receptor ERBB2 regulates mitochondrial activity on a signaling time scale.
abstract: Overexpression of the ERBB2 receptor tyrosine kinase and the mitochondrial inner membrane protein UCP2 occurs frequently in aggressive cancers with dysfunctional mitochondria. Overexpressed ERBB2 signals constitutively and elevated UCP2 can uncouple mitochondria and alleviate oxidative stress. However, the physiological contributions of UCP2 and ERBB2 at the low expression levels that are typical of most tissues, as well as the path to oncogenic deregulation, are poorly understood. We now show that ERBB2 directly controls UCP2 levels, both at low physiological levels and oncogenic overexpression. At low levels of receptor and UCP2, ligand stimulation creates a distinct temporal response pattern driven by the opposing forces of translational suppression of the exceptionally short lived UCP2 protein and a time delayed transcriptional up-regulation. The latter becomes dominant through constitutive signaling by overexpressed ERBB2, resulting in high levels of UCP2 that contribute mitochondrial uncoupling. By contrast, ligand stimulation of non-overexpressed ERBB2 transiently removes UCP2 and paradoxically reduces the mitochondrial membrane potential, oxygen consumption, and OXPHOS on a signaling time scale. However, neither the transporter activity nor down-regulation of already low UCP2 levels drive this reduction in mitochondrial activity. Instead, UCP2 is required to establish mitochondria that are capable of responding to ligand. UCP2 knockdown impairs proliferation at high glucose but its absence specifically impairs ligand-induced growth when glucose levels fluctuate. These findings demonstrate the ability of growth factor signaling to control oxidative phosphorylation on a signaling time scale and point toward a non-transporter role for low levels of UCP2 in establishing dynamic response capability.
authors.affiliation: From the Department of Biochemistry and Molecular Biology.
authors.forename: Nirav
authors.initials: N
authors.lastname: Patel
authors.forename: Antoni
authors.initials: A
authors.lastname: Barrientos
authors.forename: Ralf
authors.initials: R
authors.lastname: Landgraf
mesh_terms: D015536:Down-Regulation; D006801:Humans; D007473:Ion Channels / Q000235:genetics / Q000378:metabolism*; D008024:Ligands; D020935:MAP Kinase Signaling System; D061986:MCF-7 Cells; D053078:Membrane Potential, Mitochondrial; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D020890:Neuregulin-1 / Q000378:metabolism; D010085:Oxidative Phosphorylation; D018384:Oxidative Stress; D010101:Oxygen Consumption; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D000071246:Uncoupling Protein 2
chemical_list: D007473:Ion Channels; D008024:Ligands; D024101:Mitochondrial Proteins; D020890:Neuregulin-1; D018719:Erb-b2 Receptor Tyrosine Kinases; D000071246:Uncoupling Protein 2; C000604389:UCP2 protein, human; C117467:neuregulin beta; C508053:ERBB2 protein, human
keywords: Glucose Metabolism; Mitochondria; Receptor Tyrosine Kinase; Signal Transduction; Uncoupling Proteins