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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.

SUBMITTER: Patel N

PROVIDER: S-EPMC3853274 | biostudies-other | 2013 Dec

REPOSITORIES: biostudies-other

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The growth factor receptor ERBB2 regulates mitochondrial activity on a signaling time scale.

Patel Nirav N Barrientos Antoni A Landgraf Ralf R

The Journal of biological chemistry 20131018 49

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 t ...[more]

PMID: 24142693

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Project description:BACKGROUND:Spleen tyrosine kinase (SYK) is frequently upregulated in recurrent ovarian carcinomas, for which effective therapy is urgently needed. SYK phosphorylates several substrates, but their translational implications remain unclear. Here, we show that SYK interacts with EGFR and ERBB2, and directly enhances their phosphorylation. METHODS:We used immunohistochemistry and immunoblotting to assess SYK and EGFR phosphorylation in ovarian serous carcinomas. Association with survival was determined by Kaplan-Meier analysis and the log-rank test. To study its role in EGFR signaling, SYK activity was modulated using a small molecule inhibitor, a syngeneic knockout, and an active kinase inducible system. We applied RNA-seq and phosphoproteomic mass spectrometry to investigate the SYK-regulated EGF-induced transcriptome and downstream substrates. FINDINGS:Induced expression of constitutively active SYK130E reduced cellular response to EGFR/ERBB2 inhibitor, lapatinib. Expression of EGFRWT, but not SYK non-phosphorylatable EGFR3F mutant, resulted in paclitaxel resistance, a phenotype characteristic to SYK active ovarian cancers. In tumor xenografts, SYK inhibitor reduces phosphorylation of EGFR substrates. Compared to SYKWT cells, SYKKO cells have an attenuated EGFR/ERBB2-transcriptional activity and responsiveness to EGF-induced transcription. In ovarian cancer tissues, pSYK (Y525/526) levels showed a positive correlation with pEGFR (Y1187). Intense immunoreactivity of pSYK (Y525/526) correlated with poor overall survival in ovarian cancer patients. INTERPRETATION:These findings indicate that SYK activity positively modulates the EGFR pathway, providing a biological foundation for co-targeting SYK and EGFR. FUND: Department of Gynecology and Obstetrics, Johns Hopkins University School of Medicine, NIH/NCI, Ovarian Cancer Research Foundation Alliance, HERA Women's Cancer Foundation and Roseman Foundation. Funders had no role in the design of the study and collection, analysis, and interpretation of data and in writing the manuscript and eventually in the decision to submit the manuscript.

Project description:OBJECTIVE:A decline in mitochondrial function and biogenesis as well as increased reactive oxygen species (ROS) are important determinants of aging. With advancing age, there is a concomitant reduction in circulating levels of insulin-like growth factor-1 (IGF-1) that is closely associated with neuronal aging and neurodegeneration. In this study, we investigated the effect of the decline in IGF-1 signaling with age on astrocyte mitochondrial metabolism and astrocyte function and its association with learning and memory. METHODS:Learning and memory was assessed using the radial arm water maze in young and old mice as well as tamoxifen-inducible astrocyte-specific knockout of IGFR (GFAP-CreTAM/igfrf/f). The impact of IGF-1 signaling on mitochondrial function was evaluated using primary astrocyte cultures from igfrf/f mice using AAV-Cre mediated knockdown using Oroboros respirometry and Seahorse assays. RESULTS:Our results indicate that a reduction in IGF-1 receptor (IGFR) expression with age is associated with decline in hippocampal-dependent learning and increased gliosis. Astrocyte-specific knockout of IGFR also induced impairments in working memory. Using primary astrocyte cultures, we show that reducing IGF-1 signaling via a 30-50% reduction IGFR expression, comparable to the physiological changes in IGF-1 that occur with age, significantly impaired ATP synthesis. IGFR deficient astrocytes also displayed altered mitochondrial structure and function and increased mitochondrial ROS production associated with the induction of an antioxidant response. However, IGFR deficient astrocytes were more sensitive to H2O2-induced cytotoxicity. Moreover, IGFR deficient astrocytes also showed significantly impaired glucose and A? uptake, both critical functions of astrocytes in the brain. CONCLUSIONS:Regulation of astrocytic mitochondrial function and redox status by IGF-1 is essential to maintain astrocytic function and coordinate hippocampal-dependent spatial learning. Age-related astrocytic dysfunction caused by diminished IGF-1 signaling may contribute to the pathogenesis of Alzheimer's disease and other age-associated cognitive pathologies.

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The growth factor receptor ERBB2 regulates mitochondrial activity on a signaling time scale.

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The growth factor receptor ERBB2 regulates mitochondrial activity on a signaling time scale.

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