Annu. Rev. Biochem. 1999. 68:459–486Copyright © 1999 by Annual Reviews. All rights reserved.REGULATION OF THECYTOSKELETONANDCELLADHESION BY THERHOFAMILYGTPASES INMAMMALIANCELLSK. Kaibuchi,1S. Kuroda,1,2and M. Amano11Division of Signal Transduction, Nara Institute of Science and Technology, Ikoma 630-0101, Japan, and 2PRESTO, Japan Science and Technology, Kyoto 619-0239, Japan;e-mail: [email protected] Words G protein, protein kinase, signal transduction, guanine nucleotide, cellmorphology■ Abstract Members of the Rho family of small Ras-like GTPases—includingRhoA, -B, and -C, Rac1 and -2, and Cdc42—exhibit guanine nucleotide-bindingactivity and function as molecular switches, cycling between an inactive GDP-boundstate and an active GTP-bound state. The Rho family GTPases participate in regula-tion of the actin cytoskeleton and cell adhesion through specific targets. Identificationand characterization of these targets have begun to clarify how the Rho familyGTPases act to regulate cytoskeletal structure and cell-cell and cell-substratum con-tacts in mammalian cells. The Rho family GTPases are also involved in regulation ofsmooth muscle contraction, cell morphology, cell motility, neurite retraction, andcytokinesis. However, the molecular mechanisms by which the Rho family GTPasesparticipate in the regulation of such processes are not well established.CONTENTSIntroduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 460Molecules That Interact with Rho Family GTPases . . . . . . . . . . . . . . . . . . . . 460GDP/GTP Exchange Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 461GTPase-Activating Proteins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 463Targets/Effectors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 464Bacterial Toxins . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468Functions of the Rho Family GTPases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468Smooth Muscle Contraction and Contractility . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 468Stress Fibers and Focal Adhesions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 470Lamellipodia and Filopodia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .471Cell Motility and Migration . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473Neurite Retraction and Extension . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 475Cell-Cell Adhesion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4760066-4154/99/0701-0459$08.004598505_AR_16 11/23/99 11:14 AM Page 459460 KAIBUCHI, KURODA & AMANOMicrovilli . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 476Cytokinesis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 478Cell Transformation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479Other Functions of the Rho Family GTPases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 479Perspectives . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 480INTRODUCTIONDynamic rearrangements of the cytoskeleton and cell adhesion are required forvarious cellular processes, such as shape changes, migration, and cytokinesis(1–4). These temporal and spatial reorganizations of cell structure and cell con-tacts can be stimulated by extracellular signals, including growth factors, hor-mones, and other biologically active substances (1, 3, 4). The cytoskeleton consistsmainly of three components: actin filaments, microtubules, and intermediate fila-ments (1, 3, 4). Cell-cell contacts are mediated by adhesion molecules, such ascadherins and their associated cytoplasmic proteins, a- and b-catenins (5–7). Cell-to-substratum contact is mediated by different types of adhesion molecules, suchas integrins, and their interacting molecules, talin and vinculin (8, 9). The Rho family GTPases (including Rho, Rac, and Cdc42) participate in regu-lation of the actin cytoskeleton and various cell adhesion events (10, 11). Rho hasbeen implicated in the formation of stress fibers and focal adhesions (12), cell mor-phology (13), cell aggregation (14), cell motility (15), membrane ruffling (16),smooth muscle contraction (17, 18), neurite retraction in neuronal cells (19, 20),and cytokinesis (21, 22). Rac is involved in membrane ruffling (23), cell motility(24), actin polymerization (25), and cadherin-mediated cell-cell adhesion (26–28).Cdc42 participates …