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The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors

Oncogene volume 20, pages 6018–6025 (2001)Cite this article

Abstract

SHP-2 is a ubiquitously expressed non-transmembrane tyrosine phosphatase with two SH2 domains. Multiple reverse-genetic studies have indicated that SHP-2 is a required component for organ and animal development. SHP-2 wild-type and homozygous mutant mouse fibroblast cells in which the N-terminal SH2 domain was target-deleted were used to examine the function of SHP-2 in regulating Phosphatidylinositol 3-Kinase (PI3K) activation by growth factors. In addition, SHP-2 and various mutants were introduced into human glioblastoma cells as well as SHP-2−/− mouse fibroblasts. We found that EGF stimulation and EGFR oncoprotein (ΔEGFR) expression independently induced the co-immunoprecipitation of the p85 subunit of PI3K with SHP-2. Targeted deletion of the N-terminal SH2 domain of SHP-2 severely impaired PDGF- and IGF-induced Akt phosphorylation. Ectopic expression of SHP-2 in U87MG gliobastoma cells elevated EGF-induced Akt phosphorylation, and the effect was abolished by mutation of its N-terminal SH2 domain. Likewise, the reconstitution of SHP-2 expression in the SHP-2−/− cells enhanced Akt phosphorylation induced by EGF while rescuing that induced by PDGF and IGF. Further lipid kinase activity assays confirmed that SHP-2 modulation of Akt phosphorylation correlated with its regulation of PI3K activation. Based on these results, we conclude that SHP-2 is required for mediating PI3K/Akt activation, and the N-terminal SH2 domain is critically important for a ‘positive’ role of SHP-2 in regulating PI3K pathway activation.

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Acknowledgements

This work was supported by grants from the National Institute of Health and the Abramson Family Cancer Research Institute to MI Greene. This work was also supported by grants from the National Institutes of Health and the Department of Veteran Affairs to DM O'Rourke.

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Authors and Affiliations

  1. Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, Pennsylvania, USA

    Chuan-Jin Wu, Donald M O'Rourke, Qiang Wang & Mark I Greene

  2. Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, Pennsylvania, USA

    Chuan-Jin Wu, Qiang Wang & Mark I Greene

  3. Department of Neurosurgery, University of Pennsylvania School of Medicine, Philadelphia, PA 19104, Pennsylvania, USA

    Donald M O'Rourke

  4. The Burnham Institute, La Jolla, CA 92037, California, USA

    Gen-Sheng Feng

  5. Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892, Maryland, USA

    Gibbes R Johnson

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  1. Chuan-Jin Wu
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Correspondence to Mark I Greene.

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Wu, CJ., O'Rourke, D., Feng, GS. et al. The tyrosine phosphatase SHP-2 is required for mediating phosphatidylinositol 3-kinase/Akt activation by growth factors. Oncogene 20, 6018–6025 (2001). https://doi.org/10.1038/sj.onc.1204699

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