Paxillin alpha and Crk-associated substrate exert opposing effects on cell migration 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 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 alpha 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 alpha. Each of the phosphorylation-null mutants acts as a dominant negative for each phenotype. Moreover, we found that overexpression of paxillin alpha 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 alpha-overexpressing cells, whereas no further increment was observed in p130(Cas)-overexpressing cells. We propose that tyrosine phosphorylation of paxillin alpha and p130(Cas) exerts opposing effects on several integrin-mediated cellular events, possibly through different signaling pathways.
Department of Molecular Biology, Osaka Bioscience Institute, Suita, Osaka 565-0874, Japan.
H
H
Yano
H
H
Uchida
T
T
Iwasaki
M
M
Mukai
H
H
Akedo
K
K
Nakamura
S
S
Hashimoto
H
H
Sabe
D000818:Animals; D002455:Cell Division / Q000502:physiology*; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology*; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins / Q000502:physiology*; D051419:Paxillin; D010750:Phosphoproteins / Q000502:physiology*; D010766:Phosphorylation; D011506:Proteins; D051381:Rats; D050717:Retinoblastoma-Like Protein p130; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism*
C493843:Bcar1 protein, rat; D050719:Crk-Associated Substrate Protein; D003598:Cytoskeletal Proteins; D051419:Paxillin; D010750:Phosphoproteins; D011506:Proteins; C496063:Pxn protein, rat; D050717:Retinoblastoma-Like Protein p130; D014443:Tyrosine