The Shp-2 tyrosine phosphatase activates the Src tyrosine kinase by a non-enzymatic mechanism.
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.
Walter
A O
AO
Department of Medicine, Stanford University, California 94305, USA.
Peng
Z Y
ZY
Cartwright
C A
CA
D016475:3T3 Cells; D000818:Animals; D002471:Cell Transformation, Neoplastic; D015536:Down-Regulation; D004789:Enzyme Activation; D047908:Intracellular Signaling Peptides and Proteins; D051379:Mice; D010766:Phosphorylation; D011233:Precipitin Tests; D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases / Q000235:genetics / Q000378:metabolism*; D016392:Proto-Oncogene Proteins pp60(c-src) / Q000378:metabolism*; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases; D014443:Tyrosine / Q000378:metabolism; D018909:src Homology Domains
D047908:Intracellular Signaling Peptides and Proteins; D014443:Tyrosine; D016392:Proto-Oncogene Proteins pp60(c-src); D054592:Protein Tyrosine Phosphatase, Non-Receptor Type 11; D053824:Protein Tyrosine Phosphatase, Non-Receptor Type 6; D017027:Protein Tyrosine Phosphatases; C516725:Ptpn11 protein, mouse; C509248:Ptpn6 protein, mouse; D054593:SH2 Domain-Containing Protein Tyrosine Phosphatases