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  • Original Paper
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Shp-2 mediates v-Src-induced morphological changes and activation of the anti-apoptotic protein kinase Akt

Abstract

The protein-tyrosine phosphatase Shp-2 is a positive modulator of the Ras/mitogen-activated protein kinase pathway and a putative substrate of the transforming non-receptor tyrosine kinase v-Src. To characterize the role of Shp-2 in cellular transformation and signaling by v-Src, we expressed v-Src in normal and Shp-2-deficient mouse embryo fibroblasts. Expression of Shp-2 was found to be necessary for morphological transformation by v-Src: Shp-2+/+ cells became rounded or spindly upon v-Src expression, whereas Shp-2-deficient cells remained relatively flat. v-Src-induced reorganization of the actin cytoskeleton and the formation of podosomes were compromised in Shp-2-deficient cells. Shp-2 deficiency also reduced v-Src-induced activation of the anti-apoptotic protein kinase Akt. The reduced activation of Akt in Shp-2-deficient cells correlated with a reduction in the association of the p85 regulatory subunit of PI3-kinase with the adapter protein Cbl. Activation of PI3-kinase by v-Src may be mediated by the association of the adapter protein Cbl with the p85 subunit. Since activation of Akt is dependent on PI3-kinase, this suggests that the effect of Shp-2 on Akt activation may be mediated, at least in part, by its effects on the interaction between PI3-kinase and Cbl. The defect in activation of the Akt survival pathway also correlated with enhanced sensitivity of Shp-2-deficient cells to an apoptosis-inducing agent. These results implicate Shp-2 in v-Src-induced cytoskeletal reorganization and activation of the Akt cell survival pathway.

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Acknowledgements

We thank GS Feng (Indiana University) and T Saxton and T Pawson (Mount Sinai Hospital, Toronto, Canada) for cells. We also thank members of the Martin lab for helpful discussions. This work was supported by NIH grant CA17542 and by the facilities of the University of California Cancer Research Laboratory.

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Hakak, Y., Hsu, Y. & Martin, G. Shp-2 mediates v-Src-induced morphological changes and activation of the anti-apoptotic protein kinase Akt. Oncogene 19, 3164–3171 (2000). https://doi.org/10.1038/sj.onc.1203655

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