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Control of oligodendrocyte generation and proliferation by Shp2 protein tyrosine phosphatase.

ABSTRACT: Extracellular signals play essential roles in controlling the proliferation and differentiation of oligodendrocyte progenitor cells in the developing central nervous system. However, the intracellular pathways that transduce these extrinsic signals remain to be elucidated. In this study, we showed that conditional ablation of the nonreceptor tyrosine phosphatase Shp2 in Olig1-expressing oligodendrocyte lineage resulted in dramatic reduction in the generation and proliferation of oligodendrocyte progenitor cells in the spinal cord. Maturation and myelination of oligodendrocytes were also compromised in the Shp2 mutants. The deficits in oligodendrocyte development in Shp2 mutants nearly phenocopied those observed in PDGF-A mutants, suggesting that Shp2 is a crucial component in transducing PDGF-A signals in the control of oligodendrocyte proliferation and maturation.

SUBMITTER: Zhu Y

PROVIDER: S-EPMC3762492 | biostudies-literature | 2010 Sep

REPOSITORIES: biostudies-literature

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Control of oligodendrocyte generation and proliferation by Shp2 protein tyrosine phosphatase.

Zhu Ying Y Park Jinsil J Hu Xuemei X Zheng Kang K Li Hong H Cao Qilin Q Feng Gen-Sheng GS Qiu Mengsheng M

Glia 20100901 12

Extracellular signals play essential roles in controlling the proliferation and differentiation of oligodendrocyte progenitor cells in the developing central nervous system. However, the intracellular pathways that transduce these extrinsic signals remain to be elucidated. In this study, we showed that conditional ablation of the nonreceptor tyrosine phosphatase Shp2 in Olig1-expressing oligodendrocyte lineage resulted in dramatic reduction in the generation and proliferation of oligodendrocyte ...[more]

PMID: 20648636

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Project description:Treatment of metastasis remains a clinical challenge and the majority of breast cancer-related deaths are the result of drug-resistant metastases. The protein tyrosine phosphatase SHP2 encoded by the proto-oncogene PTPN11 promotes breast cancer progression. Inhibition of SHP2 has been shown to decrease metastases formation in various breast cancer models, but specific downstream effectors of SHP2 remain poorly characterized. Certain cytokines in the metastatic cascade facilitate local invasion and promote metastatic colonization. In this study, we investigated cytokines affected by SHP2 that could be relevant for its pro-tumorigenic properties. We used a cytokine array to investigate differentially released cytokines in the supernatant of SHP2 inhibitor-treated breast cancer cells. Expression of CXCL8 transcripts and protein abundance were assessed in human breast cancer cell lines in which we blocked SHP2 using shRNA constructs or an allosteric inhibitor. The impact of SHP2 inhibition on the phospho-tyrosine-proteome and signaling was determined using mass spectrometry. From previously published RNAseq data (Aceto et al. in Nat. Med. 18:529-37, 2012), we computed transcription factor activities using an integrated system for motif activity response analysis (ISMARA) (Balwierz et al. in Genome Res. 24:869-84, 2014). Finally, using siRNA against ETS1, we investigated whether ETS1 directly influences CXCL8 expression levels. We found that IL-8 is one of the most downregulated cytokines in cell supernatants upon SHP2 blockade, with a twofold decrease in CXCL8 transcripts and a fourfold decrease in IL-8 protein. These effects were also observed in preclinical tumor models. Analysis of the phospho-tyrosine-proteome revealed that several effectors of the mitogen-activated protein kinase (MAPK) pathway are downregulated upon SHP2 inhibition in vitro. MEK1/2 inhibition consistently reduced IL-8 levels in breast cancer cell supernatants. Computational analysis of RNAseq data from SHP2-depleted tumors revealed reduced activity of the transcription factor ETS1, a direct target of ERK and a transcription factor reported to regulate IL-8 expression. Our work reveals that SHP2 mediates breast cancer progression by enhancing the production and secretion of the pro-metastatic cytokine IL-8. We also provide mechanistic insights into the effects of SHP2 inhibition and its downstream repercussions. Overall, these results support a rationale for targeting SHP2 in breast cancer.

Dataset Information

Control of oligodendrocyte generation and proliferation by Shp2 protein tyrosine phosphatase.

Publications

Control of oligodendrocyte generation and proliferation by Shp2 protein tyrosine phosphatase.

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