Vav2 as a Rac-GDP/GTP exchange factor responsible for the nectin-induced, c-Src- and Cdc42-mediated activation of Rac.
Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules that form homo- and hetero-trans-dimers (trans-interactions). Nectins first form cell-cell contact and then recruit cadherins to the nectin-based cell-cell contact sites to form adherens junctions cooperatively with cadherins. In addition, the trans-interactions of nectins induce the activation of Cdc42 and Rac small G proteins, which enhances the formation of adherens junctions by forming filopodia and lamellipodia, respectively. The trans-interactions of nectins first recruit and activate c-Src at the nectin-based cell-cell contact sites. c-Src then phosphorylates and activates FRG, a Cdc42-GDP/GTP exchange factor (GEF) for Cdc42. The activation of both c-Src and Cdc42 by FRG is necessary for the activation of Rac, but the Rac-GEF responsible for this activation of Rac remains unknown. We showed here that the nectin-induced activation of Rac was inhibited by a dominant negative mutant of Vav2, a Rac-GEF. Nectins recruited and tyrosine-phosphorylated Vav2 through c-Src at the nectin-based cell-cell contact sites, whereas Cdc42 was not necessary for the nectin-induced recruitment of Vav2 or the nectin-induced, c-Src-mediated tyrosine phosphorylation of Vav2. Cdc42 activated through c-Src then enhanced the GEF activity of tyrosine-phosphorylated Vav2 on Rac1. These results indicate that Vav2 is a GEF responsible for the nectin-induced, c-Src-, and Cdc42-mediated activation of Rac.
Kawakatsu
Tomomi
T
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Osaka 565-0871, Japan.
Ogita
Hisakazu
H
Fukuhara
Tatsuro
T
Fukuyama
Taihei
T
Minami
Yukiko
Y
Shimizu
Kazuya
K
Takai
Yoshimi
Y
D000818:Animals; D000081247:CSK Tyrosine-Protein Kinase; D002118:Calcium / Q000378:metabolism; D002448:Cell Adhesion; D015815:Cell Adhesion Molecules / Q000737:chemistry / Q000378:metabolism*; D002460:Cell Line; D004285:Dogs; D005347:Fibroblasts / Q000378:metabolism; D005799:Genes, Dominant; D020662:Guanine Nucleotide Exchange Factors / Q000502:physiology*; D047468:Immunoprecipitation; D051379:Mice; D008856:Microscopy, Fluorescence; D008954:Models, Biological; D009154:Mutation; D000075983:Nectins; D015513:Oncogene Proteins / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D010957:Plasmids / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051567:Proto-Oncogene Proteins c-vav; D011554:Pseudopodia / Q000378:metabolism; D013997:Time Factors; D014162:Transfection; D019076:Transgenes; D014443:Tyrosine / Q000737:chemistry / Q000378:metabolism; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D019061:src-Family Kinases
D015815:Cell Adhesion Molecules; D020662:Guanine Nucleotide Exchange Factors; D000075983:Nectins; D015513:Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; C490565:Vav2 protein, mouse; D014443:Tyrosine; D011505:Protein-Tyrosine Kinases; D000081247:CSK Tyrosine-Protein Kinase; D019061:src-Family Kinases; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D002118:Calcium