Activation of Rac by cadherin through the c-Src-Rap1-phosphatidylinositol 3-kinase-Vav2 pathway.
Cadherin first forms homo-cis-dimers on the cell surface of the same cells, followed by formation of homo-trans-dimers (trans-interactions) in a Ca2+-dependent manner, eventually causing adherens junctions. In addition, trans-interacting cadherin induces activation of Rac small G protein, which stabilizes non-trans-interacting cadherin on the plasma membrane by inhibiting its endocytosis through the reorganization of the actin cytoskeleton. However, it has not fully been understood how cadherin induces the activation of Rac. We examined here the molecular mechanism of the activation of Rac by trans-interacting cadherin in fibroblasts and epithelial cells. Trans-interacting cadherin induced activation of c-Src locally at the cadherin-based cell-cell adhesion sites. c-Src then tyrosine-phosphorylated Vav2, one of the Rac-GDP/GTP exchange factors (GEFs), and induced activation of C3G, one of the Rap1-GEFs, through Crk adaptor protein, resulting in the activation of Rap1 locally at the cadherin-based cell-cell adhesion sites. The c-Src-catalysed tyrosine phosphorylation was not sufficient for the activation of Vav2 and the c-Src-induced activation of Rap1 was additionally necessary for it, although activated Rap1 alone was not sufficient for the activation of non-tyrosine-phosphorylated Vav2. This effect of Rap1 on Vav2 was mediated by phosphatidylinositol 3-kinase. We describe here the signaling pathway from trans-interacting cadherin to the activation of Rac.
Fukuyama
T
T
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita, Osaka, Japan.
Ogita
H
H
Kawakatsu
T
T
Inagaki
M
M
Takai
Y
Y
D000199:Actins / Q000737:chemistry / Q000378:metabolism; D000256:Adenoviridae / Q000235:genetics; D000730:Androstadienes / Q000494:pharmacology; D000818:Animals; D015820:Cadherins / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D002460:Cell Line; D002462:Cell Membrane / Q000378:metabolism; D003599:Cytoskeleton / Q000378:metabolism; D004247:DNA / Q000378:metabolism; D019281:Dimerization; D004285:Dogs; D004705:Endocytosis; D004789:Enzyme Activation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004847:Epithelial Cells / Q000166:cytology; D005347:Fibroblasts / Q000378:metabolism; D020735:Guanine Nucleotide-Releasing Factor 2 / Q000378:metabolism; D047468:Immunoprecipitation; D051379:Mice; D008856:Microscopy, Fluorescence; D008957:Models, Genetic; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D050737:Proto-Oncogene Proteins c-crk / Q000378:metabolism; D051567:Proto-Oncogene Proteins c-vav / Q000378:metabolism*; D015398:Signal Transduction; D013997:Time Factors; D015533:Transcriptional Activation; D014162:Transfection; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D000077191:Wortmannin; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020827:rap1 GTP-Binding Proteins / Q000378:metabolism*
D000199:Actins; D000730:Androstadienes; D015820:Cadherins; D004791:Enzyme Inhibitors; D020735:Guanine Nucleotide-Releasing Factor 2; D050737:Proto-Oncogene Proteins c-crk; D051567:Proto-Oncogene Proteins c-vav; C093651:VAV2 protein, human; C490565:Vav2 protein, mouse; D014443:Tyrosine; D004247:DNA; D019869:Phosphatidylinositol 3-Kinases; D020744:rac GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins; D002118:Calcium; D000077191:Wortmannin