Transformation Suppression by Protein Tyrosine Phosphatase 1B Requires a Functional SH3 Ligand

Abstract

ABSTRACT We have recently shown that protein tyrosine phosphatase 1B (PTP1B) associates with the docking protein p130 Cas in 3Y1 rat fibroblasts. This interaction is mediated by a proline-rich sequence on PTP1B and the SH3 domain on p130 Cas . Expression of wild-type PTP1B (WT-PTP1B), but not a catalytically competent, proline-to-alanine point mutant that cannot bind p130 Cas (PA-PTP1B), causes substantial tyrosine dephosphorylation of p130 Cas (F. Liu, D. E. Hill, and J. Chernoff, J. Biol. Chem. 271:31290–31295, 1996). Here we demonstrate that WT-, but not PA-PTP1B, inhibits transformation of rat 3Y1 fibroblasts by v- crk , - src , and - ras , but not by v- raf . These effects on transformation correlate with the phosphorylation status of p130 Cas and two proteins that are associated with p130 Cas , Paxillin and Fak. Expression of WT-PTP1B reduces formation of p130 Cas -Crk complexes and inhibits mitogen-activated protein kinase activation by Src and Crk. These data show that transformation suppression by PTP1B requires a functional SH3 ligand and suggest that p130 Cas may represent an important physiological target of PTP1B in cells.