Shp-2 mediates v-Src-induced morphological changes and activation of the anti-apoptotic protein kinase Akt.
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.
Hakak
Y
Y
Department of Molecular and Cell Biology, University of California, Berkeley 94720-3204, USA.
Hsu
Y S
YS
Martin
G S
GS
D000818:Animals; D017209:Apoptosis; D002478:Cells, Cultured; D003599:Cytoskeleton; D004789:Enzyme Activation; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D015688:Oncogene Protein pp60(v-src) / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D015688:Oncogene Protein pp60(v-src); D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse