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The Shp-2 tyrosine phosphatase activates the Src tyrosine kinase by a non-enzymatic mechanism

Oncogene volume 18, pages 1911–1920 (1999)Cite this article

Abstract

Previously, we demonstrated that the Src tyrosine kinase interacts with the Shp-2 tyrosine phosphatase. To determine whether Shp-2 regulates Src kinase activity, we measured Src activity in cells overexpressing wild-type or catalytically-inactive C463S Shp-2. We observed a 2 – 3-fold increase in the specific activity of Src in both cell types and the increase did not appear to be due to dephosphorylation of Tyr 527 or phosphorylation of Tyr 416 on Src. Conversely, we observed a 2 – 3-fold decrease in the specific activity of Src when Shp-2 expression was inhibited. Using glutathione S-transferase-fusion proteins, we demonstrated that Shp-2 binds to the SH3 domain of Src. Our findings reveal that the Shp-2 tyrosine phosphatase can regulate the Src tyrosine kinase by a non-enzymatic mechanism. We also found that the phosphatase activity of Shp-2 immunoprecipitates is downregulated in cells transformed by Src or other proteins, and that Shp-2 preferentially associates with the membrane fraction of transformed cells. We suggest that membrane-association of Shp-2 is important for regulating Shp-2 activity.

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Acknowledgements

We thank Rachel Harte for assistance with experiments and Rachel Harte and Karen Conroy for help with analysing data and preparing figures. We thank Tony Pawson for the gift of pBS-Shp-2, Sara Courtneidge for kindly providing the ΔSH3 src mutant, David Shalloway for v-Src transformed NIH3T3 cells, Amato Giaccia for Ha-Ras[V12]-transformed NIH3T3 cells and Joosang Park for generating pGEXsrc plasmids. This work was supported initially by an American Cancer Society Grant BE-246 and then by a National Institutes of Health (NIH) Grant 2R01 DK43743-07 (to CAC), a Deutsche Forschungsgemeinschaft Postdoctoral Fellowship Award (to AOW) and a NIH NIDDK Training Grant T32 DK07056 (Z-YP).

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  1. Department of Medicine, Standford University, Stanford, 94305, California, USA

    Annette O Walter, Zao-Yuan Peng & Christine A Cartwright

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  1. Annette O Walter
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Walter, A., Peng, ZY. & Cartwright, C. The Shp-2 tyrosine phosphatase activates the Src tyrosine kinase by a non-enzymatic mechanism. Oncogene 18, 1911–1920 (1999). https://doi.org/10.1038/sj.onc.1202513

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