TRANSFORMATION SUPPRESSION BY PROTEIN-TYROSINE-PHOSPHATASE 1B REQUIRES A FUNCTIONAL SH3 LIGAND

We have recently shown that protein tyrosine phosphatase 1B (PTP1B) as sociates with the docking protein p130(Cas) in 3Y1 rat fibroblasts, Th is interaction is mediated by a proline-rich sequence on PTP1B and the SN3 domain on p130(Cas), Expression of wild-type PTP1B (WT-PTP1B), bu t not a catalytically competent, proline-to-alanine point mutant that cannot bind p130(Cas) (PA-PTP1B), causes substantial tyrosine dephosph orylation of p130(Cas) (F, Liu, D, E, Hill, and J, Chernoff J. Biol. C hem, 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 r educes formation of p130(Cas)-Crk complexes and inhibits mitogen-activ ated protein kinase activation by Src and Crk. These data show that tr ansformation suppression by PTP1B requires a functional SH3 ligand and suggest that p130(Cas) may represent an important physiological targe t of PTP1B in cells.