Roles of cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1.
Gab-1 is a multiple docking protein that is tyrosine phosphorylated by receptor tyrosine kinases such as c-Met, hepatocyte growth factor/scatter factor receptor, and epidermal growth factor receptor. We have now demonstrated that cell-cell adhesion also induces marked tyrosine phosphorylation of Gab-1 and that disruption of cell-cell adhesion results in its dephosphorylation. An anti-E-cadherin antibody decreased cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1, whereas the expression of E-cadherin specifically induced tyrosine phosphorylation of Gab-1. A relatively selective inhibitor of Src family kinases reduced cell-cell adhesion-dependent tyrosine phosphorylation of Gab-1, whereas expression of a dominant-negative mutant of Csk increased it. Disruption of cell-cell adhesion, which reduced tyrosine phosphorylation of Gab-1, also reduced the activation of mitogen-activated protein kinase and Akt in response to cell-cell adhesion. These results indicate that E-cadherin-mediated cell-cell adhesion induces tyrosine phosphorylation by a Src family kinase of Gab-1, thereby regulating the activation of Ras/MAP kinase and phosphatidylinositol 3-kinase/Akt cascades.
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, 2-2 Yamada-oka, Suita 565-0871, Japan.
M
M
Shinohara
A
A
Kodama
T
T
Matozaki
A
A
Fukuhara
K
K
Tachibana
H
H
Nakanishi
Y
Y
Takai
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D015820:Cadherins / Q000276:immunology; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D004789:Enzyme Activation; D005799:Genes, Dominant; D005982:Glutathione Transferase / Q000378:metabolism; D015151:Immunoblotting; D020935:MAP Kinase Signaling System; D051379:Mice; D009154:Mutation; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011233:Precipitin Tests; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000378:metabolism; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism*; D018631:ras Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D015820:Cadherins; D002118:Calcium; D005982:Glutathione Transferase; D019869:Phosphatidylinositol 3-Kinases; D010750:Phosphoproteins; D011993:Recombinant Fusion Proteins; D014443:Tyrosine; D018631:ras Proteins; C490897:Gab1 protein, mouse