Protein-tyrosine Phosphatase α Regulates Src Family Kinases and Alters Cell-Substratum Adhesion*

The roles of protein-tyrosine phosphatases (PTPs) in processes such as cell growth and adhesion are poorly understood. To explore the ability of specific PTPs to regulate cell signaling pathways initiated by stimulation of growth factor receptors, we expressed the receptor-like PTP, PTPα, in A431 epidermoid carcinoma cells. These cells express high levels of the epidermal growth factor (EGF) receptor and proliferate in response to the autocrine production of transforming growth factor-α. Conversely, EGF stimulation of A431 cells in vitro leads to growth inhibition and triggers the rapid detachment of these cells from the substratum. Although PTPα expression did not alter the growth characteristics of either unstimulated or EGF-stimulated cells, this phosphatase was associated with increased cell-substratum adhesion. Furthermore, PTPα-expressing A431 cells were strikingly resistant to EGF-induced cell rounding. Overexpression of PTPα in A431 cells was associated with the dephosphorylation/activation of specific Src family kinases, suggesting a potential mechanism for the observed alteration in A431 cell-substratum adhesion. Src kinase activation was dependent on the D1 catalytic subunit of PTPα, and there was evidence of association between PTPα and Src kinase(s). PTPα expression also led to increased association of Src kinase with the integrin-associated focal adhesion kinase, pp125FAK. In addition, paxillin, a Src and/or pp125FAK substrate, displayed increased levels of tyrosine phosphorylation in PTPα-expressing cells and was associated with elevated amounts of Csk. In view of these alterations in focal adhesion-associated molecules in PTPα-expressing A431 cells, as well as the changes in adhesion demonstrated by these cells, we propose that PTPα may have a role in regulating cell-substratum adhesion.