PROTEIN-TYROSINE-PHOSPHATASE 1B NEGATIVELY REGULATES INTEGRIN SIGNALING

Protein tyrosine phosphatase (PTP) 1B has long been known to regulate cell proliferation negatively, but the mechanism by which this inhibit ion occurs is poorly defined. We have shown previously that PTP1B bind s to, and dephosphorylates, p130(Cas) (Crk-associated substrate) [1], a protein that is thought to play a role in integrin signaling [2,3]. In this report, we present evidence that PTP1B interferes specifically with cell-adhesion-stimulated, but not growth-factor-stimulated, sign aling pathways. In rat fibroblasts that overexpress PTP1B, the activat ion of mitogen-activated protein (MAP) kinase by growth factors was no t affected, but activation by cell adhesion was markedly impaired. The inhibition of adhesion-dependent MAP kinase activation by PTP1B requi red an intact proline-rich region in the carboxyl terminus of PTP1B, a region we have shown to mediate binding to the Src-homology 3 (SH3) d omain of p130(Cas) [1]. Overexpression of wild-type PTP1B, but not of a proline-to-alanine mutant form (PA-PTP1B) that is unable to bind or dephosphorylate p130(Cas), interfered with cell spreading, cytoskeleta l architecture, and the formation of focal adhesion complexes. Cells o verexpressing wild-type PTP1B also displayed markedly reduced migratio n in response to a fibronectin gradient, whereas cells expressing the PA-PTP1B mutant migrated normally. These data indicate that PTP1B exer ts its inhibitory effects via proline-dependent interactions with one or more critical components of the adhesion-dependent signaling appara tus, and suggest that one of these components may be p130(Cas). (C) Cu rrent Biology Ltd.