Paxillin α and Crk-associated substrate exert opposing effects on cell migration and contact inhibition of growth through tyrosine phosphorylation

Abstract

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.

FAK engages multiple pathways to maintain survival of fibroblasts and epithelia – differential roles for paxillin and p130Cas

“…In MDCK cells, paxillin controls cell migration, whereas in other cell types p130Cas is required (Lamorte et al, 2003;Petit et al, 2000;Schlaepfer et al, 1994;Yano et al, 2000). Our data show that p130Cas is not required for FAK-dependent survival in epithelial cells.…”

Expression levels of the focal adhesion-associated proteins paxillin and p130CAS in canine and feline mammary tumors

“…Many studies using different approaches to address the role of paxillin in the cell have produced the same conclusion that paxillin controls cell spreading and motility [23]. Overexpression of wild type paxillin inhibits the ability of lysophosphatidic acid stimulated MM-1 rat hepatoma tumor cells to invade a monolayer of primary mesothelial cells [29]. Paxillin has also been implicated in the control of cell spreading and motility by the α 4 integrin subunit [11], since an α 4 mutant defective for paxillin binding failed to block cell spreading.…”

SLK-mediated phosphorylation of paxillin is required for focal adhesion turnover and cell migration

“…The composition of focal adhesions has been shown to vary over time depending on its acquired level of maturity. For example, focal complexes, which are integral to the formation of lamellipodial and filopodial extensions, have been shown to express relatively low to non-existent levels of proteins that are more prevalent in stable adhesions such as paxillin and zyxin, respectively [48][49][50]. However, the heterogeneity of the adhesion complex does not end with differential protein composition and localization.…”