Paxillin alpha and Crk-associated substrate exert opposing effects on cellmigration and contact inhibition of growth through tyrosine phosphorylation

Protein tyrosine phosphorylation accompanies and is essential for integrin signaling. We have shown that tyrosine phosphorylation of paxillin alpha an d Crk-associated substrate (p130(Cas)) is a prominent event on integrin act ivation in normal murine mammary gland epithelial cells. Tyrosine phosphory lation of p130(Cas) has been demonstrated to facilitate cell migration. We show here that tyrosine phosphorylation of paxillin alpha acts to reduce ha ptotactic cell migrations as well as transcellular invasive activities in s everal different experimental cell systems, whereas tyrosine phosphorylatio n of p130(Cas) exerts opposing effects to those of paxillin alpha, Each of the phosphorylation-null mutants acts as a dominant negative for each pheno type, Moreover, we found that overexpression of paxillin alpha reduced the cell saturation density of normal murine mammary gland cells, whereas overe xpression of p130(Cas) increased it. These effects also seemed to depend on tyrosine phosphorylation events, Cell growth rates and morphologies at gro wing phases were not significantly altered, nor were cells transformed. Add ition of epidermal growth factor increased saturation density of the paxill in alpha-overexpressing cells, whereas no further increment was observed in p130(Cas)-overexpressing cells. We propose that tyrosine phosphorylation o f paxillin alpha and p130(Cas) exerts opposing effects on several integrin- mediated cellular events, possibly through different signaling pathways.