Common signaling pathway is used by the trans-interaction of Necl-5/Tage4/PVR/CD155 and nectin, and of nectin and nectin during the formation of cell-cell adhesion.
Nectin is a Ca2+-independent Ig-like cell-cell adhesion molecule that forms homo- and hetero-trans-dimers (trans-interaction). Nectin first forms cell-cell adhesions and then recruits cadherin to the nectin-based cell-cell adhesion sites to form AJ cooperatively with cadherin. In addition, the trans-interaction of nectin and nectin induces the activation of Cdc42 and Rac small G proteins, which enhances the formation of AJ. The activation of Cdc42 and Rac by the trans-interaction of nectin and nectin is mediated by c-Src, another small G protein, Rap1, a Cdc42-GEF, FRG, and a Rac-GEF, Vav2. Necl-5/Tage4/PVR/CD155 is another Ca2+-independent Ig-like molecule, which does not homophilically trans-interact, but heterophilically trans-interacts with nectin-3, one member of the nectin family. We show here that the trans-interaction of Necl-5 and nectin-3 bidirectionally induces the activation of Cdc42 and Rac. Similarly to the activation of Cdc42 and Rac by the trans-interaction of nectin and nectin, the trans-interaction of Necl-5 and nectin-3 first recruits and activates c-Src at the Necl-5/nectin-3-based cell-cell contact sites. c-Src then phosphorylates FRG and Vav2, and the tyrosine-phosphorylated FRG and Vav2 are recruited to the Necl-5/nectin-3-based cell-cell contact sites. The trans-interaction of Necl-5 and nectin-3 also activates Rap1 through C3G, a Rap-GEF, and this activation of Rap1 is required for the activation of Cdc42 and Rac. These results indicate that the trans-interactions of Necl-5 and nectin-3 and of nectin and nectin induce the activation of Cdc42 and Rac through the common signaling molecules c-Src, Rap1, FRG, and Vav2.
Sato
Tatsuhiro
T
Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine, Faculty of Medicine, Suita 565-0871, Japan.
Irie
Kenji
K
Okamoto
Ryoko
R
Ooshio
Takako
T
Fujita
Naoyuki
N
Takai
Yoshimi
Y
D000818:Animals; D002448:Cell Adhesion / Q000235:genetics* / Q000502:physiology*; D015815:Cell Adhesion Molecules / Q000502:physiology*; D002465:Cell Movement; D006801:Humans; D008565:Membrane Proteins / Q000502:physiology*; D000075983:Nectins; D015513:Oncogene Proteins / Q000502:physiology; D051567:Proto-Oncogene Proteins c-vav; D011554:Pseudopodia / Q000502:physiology; D051381:Rats; D011991:Receptors, Virus / Q000502:physiology*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000502:physiology; D020744:rac GTP-Binding Proteins / Q000502:physiology; D020827:rap1 GTP-Binding Proteins / Q000502:physiology
D015815:Cell Adhesion Molecules; D008565:Membrane Proteins; C000619014:NECTIN3 protein, human; D000075983:Nectins; D015513:Oncogene Proteins; D051567:Proto-Oncogene Proteins c-vav; D011991:Receptors, Virus; C093651:VAV2 protein, human; C066100:poliovirus receptor; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020827:rap1 GTP-Binding Proteins