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Protein tyrosine phosphorylation accompanies and is essential for integrin signaling. We have shown that tyrosine phosphorylation of paxillin ␣ and Crk-associated substrate (p130 Cas ) is a prominent event on integrin activation in normal murine mammary gland epithelial cells. Tyrosine phosphorylation of p130 Cas has been demonstrated to facilitate cell migration. We show here that tyrosine phosphorylation of paxillin ␣ acts to reduce haptotactic cell migrations as well as transcellular invasive activities in several different experimental cell systems, whereas tyrosine phosphorylation of p130 Cas exerts opposing effects to those of paxillin ␣. Each of the phosphorylation-null mutants acts as a dominant negative for each phenotype. Moreover, we found that overexpression of paxillin ␣ reduced the cell saturation density of normal murine mammary gland cells, whereas overexpression of p130 Cas increased it. These effects also seemed to depend on tyrosine phosphorylation events. Cell growth rates and morphologies at growing phases were not significantly altered, nor were cells transformed. Addition of epidermal growth factor increased saturation density of the paxillin ␣-overexpressing cells, whereas no further increment was observed in p130 Cas -overexpressing cells. We propose that tyrosine phosphorylation of paxillin ␣ and p130 Cas exerts opposing effects on several integrin-mediated cellular events, possibly through different signaling pathways.

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