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Published online 26 July 2004. doi:10.1083/jcb.200401093
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 166, Number 3, 393-405
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Article

Activation of Cdc42 by trans interactions of the cell adhesion molecules nectins through c-Src and Cdc42-GEF FRG



Tatsuro Fukuhara1, Kazuya Shimizu1, Tomomi Kawakatsu1, Taihei Fukuyama1, Yukiko Minami1, Tomoyuki Honda1, Takashi Hoshino1, Tomohiro Yamada1, Hisakazu Ogita1, Masato Okada2, and Yoshimi Takai1

1 Department of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine
2 Department of Oncogene Research, Research Institute for Microbial Diseases, Osaka University, Suita 565-0871, Osaka, Japan

Address correspondence to Yoshimi Takai, Dept. of Molecular Biology and Biochemistry, Osaka University Graduate School of Medicine/Faculty of Medicine, Suita 565-0871, Osaka, Japan. Tel.: 81-6-6879-3410. Fax: 81-6-6879-3419. email: ytakai{at}molbio.med.osaka-u.ac.jp

Nectins, Ca2+-independent immunoglobulin-like cell–cell adhesion molecules, initiate cell–cell adhesion by their trans interactions and recruit cadherins to cooperatively form adherens junctions (AJs). In addition, the trans interactions of nectins induce the activation of Cdc42 and Rac small G proteins, which increases the velocity of the formation of AJs. We examined here how nectins induce the activation of Cdc42 in MDCK epithelial cells and L fibroblasts. Nectins recruited and activated c-Src at the nectin-based cell–cell adhesion sites. FRG, a GDP/GTP exchange factor specific for Cdc42, was then recruited there, tyrosine phosphorylated by c-Src, and activated, causing an increase in the GTP-bound active form of Cdc42. Inhibition of the nectin-induced activation of c-Src suppressed the nectin-induced activation of FRG and Cdc42. Inhibition of the nectin-induced activation of FRG or depletion of FRG by RNA interference suppressed the nectin-induced activation of Cdc42. These results indicate that nectins induce the activation of Cdc42 through c-Src and FRG locally at the nectin-based cell–cell adhesion sites.

Key Words: Src family kinases; GDP/GTP exchange factors; small G proteins; intracellular signaling; adherens junctions

Abbreviations used in this paper: AJ, adherens junction; ConA, concanavalin A; CRIB, Cdc42 and Rac interactive binding domain; Csk, COOH-terminal Src kinase; DS, desmosome; FRET, fluorescent resonance energy transfer; GEF, GDP/GTP exchange factor; pAb, polyclonal antibody; PLL, poly-L-lysine; SFK, Src family kinase; siRNA, small interfering RNA; TJ, tight junction.


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