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The control of oligodendrocyte bioenergetics by interferon-gamma (IFN-?) and Src homology region 2 domain-containing phosphatase-1 (SHP-1).

ABSTRACT: Glycolysis and mitochondrial respiration are essential for oligodendrocyte metabolism in both the developing and adult CNS. Based on recent reports on the effects of the proinflammatory cytokine IFN-? on metabolism and on oligodendrocytes, we addressed whether IFN-? may affect oligodendrocyte bioenergetics in ways relevant to CNS disease. Oligodendrocytes of mice treated with IFN-? showed significant reductions in aerobic glycolysis and mitochondrial respiration. As expected, IFN-? treatment led to the induction of STAT1 in oligodendrocytes indicating active signaling into these cells. To determine the direct effects of IFN-? on oligodendrocyte metabolism, cultured oligodendrocytes were treated with IFN-? in vitro, which resulted in suppression of glycolysis similar to oligodendrocytes of animals treated with IFN-? in vivo. Mice lacking SHP-1, a key regulator of IFN-? and STAT1 signaling in CNS glia, had high constitutive levels of STAT1 and decreased aerobic glycolysis and mitochondrial respiration rates relative to wild type mouse oligodendrocytes. Together, these data show that IFN-? and SHP-1 control oligodendrocyte bioenergetics in ways that may relate to the role of this cytokine in CNS disease.

SUBMITTER: Minchenberg SB

PROVIDER: S-EPMC5924629 | biostudies-literature | 2019 Jun

REPOSITORIES: biostudies-literature

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The control of oligodendrocyte bioenergetics by interferon-gamma (IFN-γ) and Src homology region 2 domain-containing phosphatase-1 (SHP-1).

Minchenberg Scott B SB Massa Paul T PT

Journal of neuroimmunology 20171028

Glycolysis and mitochondrial respiration are essential for oligodendrocyte metabolism in both the developing and adult CNS. Based on recent reports on the effects of the proinflammatory cytokine IFN-γ on metabolism and on oligodendrocytes, we addressed whether IFN-γ may affect oligodendrocyte bioenergetics in ways relevant to CNS disease. Oligodendrocytes of mice treated with IFN-γ showed significant reductions in aerobic glycolysis and mitochondrial respiration. As expected, IFN-γ treatment led ...[more]

PMID: 29113698

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Project description:SHP-2 is a tyrosine phosphatase expressed in most embryonic and adult tissues. SHP-2 regulates many cellular functions including growth, differentiation, migration, and survival. Genetic and biochemical evidence show that SHP-2 is required for rat sarcoma viral oncogene/extracellular signal-regulated kinases mitogen-activated protein kinase pathway activation by most tyrosine kinase receptors, as well as by G-protein-coupled and cytokine receptors. In addition, SHP-2 can regulate the Janus kinase/signal transducers and activators of transcription, nuclear factor-?B, phosphatidyl-inositol 3-kinase/Akt, RhoA, Hippo, and Wnt/?-catenin signaling pathways. Emerging evidence has shown that SHP-2 dysfunction represents a key factor in the pathogenesis of gastrointestinal diseases, in particular in chronic inflammation and cancer. Variations within the gene locus encoding SHP-2 have been associated with increased susceptibility to develop ulcerative colitis and gastric atrophy. Furthermore, mice with conditional deletion of SHP-2 in intestinal epithelial cells rapidly develop severe colitis. Similarly, hepatocyte-specific deletion of SHP-2 induces hepatic inflammation, resulting in regenerative hyperplasia and development of tumors in aged mice. However, the SHP-2 gene initially was suggested to be a proto-oncogene because activating mutations of this gene were found in pediatric leukemias and certain forms of liver and colon cancers. Moreover, SHP-2 expression is up-regulated in gastric and hepatocellular cancers. Notably, SHP-2 functions downstream of cytotoxin-associated antigen A (CagA), the major virulence factor of Helicobacter pylori, and is associated with increased risks of gastric cancer. Further compounding this complexity, most recent findings suggest that SHP-2 also coordinates carbohydrate, lipid, and bile acid synthesis in the liver and pancreas. This review aims to summarize current knowledge and recent data regarding the biological functions of SHP-2 in the gastrointestinal tract.

Project description:BACKGROUND: Epidermal growth factor receptor (EGFR) signalling is frequently altered during glioblastoma de novo pathogenesis. An important downstream modulator of this signal cascade is SHP2 (Src homology domain-containing phosphatase 2). METHODS: We examined the The Cancer Genome Atlas (TCGA) database for SHP2 mutations. We also examined the expression of a further 191 phosphatases in the TCGA database and used principal component and comparative marker analysis available from the Broad Institute to recapitulate the TCGA-defined subgroups and identify the specific phosphatases defining each subgroup. We identified five siRNAs from two independent commercial sources that were reported by the vendor to be pre-optimised in their specificity of SHP2 silencing. The specificity and physiological effects of these siRNAs were tested using an in vitro glioma model. RESULTS: TCGA data demonstrate SHP2 to be mutated in 2% of the glioblastoma multiforme's studied. Both mutations identified in this study are likely to be activating mutations. We found that the four subgroups of GBM as defined by TCGA differ significantly with regard to the expression level of specific phosphatases as revealed by comparative marker analysis. Surprisingly, the four subgroups can be defined solely on the basis of phosphatase expression level by principal component analysis. This result suggests that critical phosphatases are responsible for the modulation of specific molecular pathways within each subgroup. Src homology domain-containing phosphatase 2 constitutes one of the 12 phosphatases that define the classical subgroup. We confirmed the biological significance by siRNA knockdown of SHP2. All five siRNAs tested reduced SHP2 expression by 70-100% and reduced glioblastoma cell line growth by up to 80%. Profiling the established molecular targets of SHP2 (ERK1/2 and STAT3) confirmed specificity of these siRNAs. The loss of cell viability induced by SHP2 silencing could not be explained by a significant increase in apoptosis alone as demonstrated by terminal deoxyribonucleotidyl transferase-mediated nick-end labelling and propidium iodide staining. Src homology domain-containing phosphatase 2 silencing, however, did induce an increase in β-galactosidase staining. Propidium iodide staining also showed that SHP2 silencing increases the population of glioblastoma cells in the G1 phase of the cell cycle and reduces the population of such cells in the G2/M- and S-phase. CONCLUSION: Src homology domain-containing phosphatase 2 promotes the growth of glioblastoma cells by suppression of cellular senescence, a phenomenon not described previously. Selective inhibitors of SHP2 are commercially available and may be considered as a strategy for glioblastoma therapy.

Dataset Information

The control of oligodendrocyte bioenergetics by interferon-gamma (IFN-?) and Src homology region 2 domain-containing phosphatase-1 (SHP-1).

Publications

The control of oligodendrocyte bioenergetics by interferon-gamma (IFN-γ) and Src homology region 2 domain-containing phosphatase-1 (SHP-1).

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