BREAKTHROUGHS AND VIEWS Cdc42, Rac1, and Their Effector IQGAP1 as Molecular Switches for Cadherin-Mediated Cell–Cell Adhesion 1 Shinya Kuroda,* , † Masaki Fukata,* , ‡ Masato Nakagawa,* and Kozo Kaibuchi* *Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma 630-0101, Japan; †Inheritance and Variation Group, PRESTO, Japan Science and Technology, Kyoto 619-0237, Japan; and ‡Department of Biochemistry, Hiroshima University School of Medicine, Hiroshima 734-8551, Japan Received July 7, 1999 Cell– cell adhesion is a dynamic process in various cellular and developmental situations. Cadherins, well-known Ca 2 -dependent adhesion molecules, are thought to play a major role in the regulation of cell– cell adhesion. However, the molecular mechanism un- derlying the rearrangement of cadherin-mediated cell– cell adhesion is largely unknown. Cdc42 and Rac1, belonging to the Rho small GTPase family, have recently been shown to be involved in the regulation of cell– cell adhesion. In addition, IQGAP1, an effector for Cdc42 and Rac1, has been shown to regulate the cadherin function through interaction with -catenin, a molecule associated with cadherin. In this review, we will summarize the mode of action of Cdc42 and Rac1 as well as IQGAP1 as molecular switches for the cadherin function, and then discuss physiological pro- cesses in which the Cdc42/Rac1/IQGAP1 system may be involved. © 1999 Academic Press I. E-CADHERIN AND ITS ASSOCIATED MOLECULES -CATENIN AND -CATENIN E-cadherin, belonging to the classic cadherins, is a Ca 2+ -dependent homophilic cell– cell adhesion mole- cule that is required for cell– cell adhesion and epithe- lial cell polarity (1–3). Strong adhesion of E-cadherin requires linkage of its cytoplasmic domain to the actin cytoskeleton (4 – 6). This linkage is mediated by direct interaction of -catenin or plakoglobin/-catenin with the cytoplasmic domain of E-cadherin (4 – 6). -Catenin and plakoglobin also interact with -catenin. -catenin has been thought to link the cadherin/-catenin/ -catenin complex (cadherin/catenins complex) to the actin cytoskeleton directly or indirectly. There is evi- dence that the association of -catenin with the E-cadherin/-catenin complex is essential for the E-cadherin-mediated cell– cell adhesion (7, 8). For in- stance, PC9 cells, lacking the expression of -catenin, do not form cell– cell adhesion, but the ectopic expres- sion of -catenin in PC9 cells restores E-cadherin- mediated cell– cell adhesion (7, 8). Thus, -catenin is a key regulator of the cadherin/catenins complex. Cell– cell adhesion seems to be a very static process and it is difficult to imagine that there is dynamic remodeling as long as fixed cells are used. However, it has been shown that, in confluent conditions, L cells stably expressing E-cadherin (EL cells), exhibit facili- tated intercellular motility, while L cells stably ex- pressing E-cadherin and -catenin chimeric molecule (nEL cells), exhibit suppressed intercellular motility, compared to parental L cells (9). Time-lapse video mi- croscopic analysis has revealed that the cell– cell adhe- sion of EL cells is a dynamic process, and EL cells repeatedly attach to and detach from the adjacent EL cells, whereas the cell– cell adhesion of nEL cells is very stable, and the cell– cell adhesion once established appears to be rarely disrupted in nEL cells (9). In addition, dynamic rearrangement in the cell– cell ad- hesion can be seen in other cell lines including Madin- Darby canine kidney (MDCK) cells. MDCK cells rap- idly migrate even in confluent conditions, indicating that the cell– cell adhesion process is transiently per- turbed at migrating areas, enabling dynamic migra- tion. 2 Therefore, the cell– cell adhesion is being con- stantly rearranged in real time, suggesting that the cadherin/catenins complex is dynamically remodeled. 1 The original work by the authors has been supported by the Japan Society of the Promotion of Science Research for the Future, by the Ministry of Education, Science, and Culture, Japan (1998), by the Human Frontier Science Program, and by a grant from Kirin Brewery Company Limited. 2 A detailed analysis will be described elsewhere. Biochemical and Biophysical Research Communications 262, 1– 6 (1999) Article ID bbrc.1999.1122, available online at http://www.idealibrary.com on 1 0006-291X/99 $30.00 Copyright © 1999 by Academic Press All rights of reproduction in any form reserved.