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

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.

ACKNOWLEDGMENTS

We thank Gary Kruh for 3Y1 and 3Y1-v-crk cells and M. Scheurmann and H. Hanafusa for pMSE and pCT10 plasmids, respectively.

This work was supported by grants from the National Institutes of Health (RO1 CA58836), by CORE Grant CA-06927, and by US Healthcare, as well as by an appropriation from the Commonwealth of Pennsylvania.