Rho GTPase Signaling in the Development of Colorectal Cancer Fernanda Leve and Jose ´ A. Morgado-Dı ´az * Grupo de Biologia Estrutural, Divisa ˜o de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Ca ˆ ncer–INCa, Rio de Janeiro 2231050, Brazil ABSTRACT The involvement of Rho GTPases in major aspects of cancer development, such as cell proliferation, apoptosis, cell polarity, adhesion, migration, and invasion, have recently been attracting increasing attention. In this review, we have summarized the current findings in the literature, and we discuss the participation of the Rho GTPase members RhoA, Rac1, and Cdc42 in the development of colorectal cancer, the second most lethal neoplasia worldwide. First, we present an overview of the mechanisms of Rho GTPase regulation and the impact that regulator proteins exert on GTPase signaling. Second, we focus on the participation of Rho GTPases as modulators of colorectal cancer development. Third, we emphasize the involvement of activation and expression alterations of Rho GTPases in events associated with cancer progression, such as loss of cell–cell adhesion, proliferation, migration, and invasion. Finally, we highlight the potential use of novel anticancer drugs targeting specific components of the Rho GTPase signaling pathway with antineoplastic activity in this cancer type. J. Cell. Biochem. 113: 2549–2559, 2012. ß 2012 Wiley Periodicals, Inc. KEY WORDS: Rho GTPases; COLORECTAL CANCER; ACTIN CYTOSKELETON; TUMOR PROGRESSION; CELL–CELL ADHESION; CELL SIGNALING R ho GTPases belong to the Ras superfamily of small GTPases, which includes the Ras, Ran, Rab, Arf, Rheb, and Rho families. These proteins were initially described over three decades ago as eukaryotic targets of Clostridium botulinum exotoxins. Since that time, a great number of biochemical, cell biological, and physiological studies have demonstrated that Rho GTPases as crucial regulators of cellular homeostasis during both normal and disease conditions [reviewed in Vega and Ridley, 2008]. Mammalian cells express 22 Rho GTPases, including three Rho isoforms (A, B, and C), three Rac isoforms (1, 2, and 3), and Cdc42, which have been the subject of intense investigation. Despite the fact that Rho, Rac, and Cdc42 catalyze identical chemical reactions (see below) and can target the same cellular structures, their functional effects can be vastly different. For example, Rho activation induces the assembly of basal stress fibers in cytoskeleton-driven alterations of cell motility, while increases in Rac and Cdc42 activity result in the formation of lamellipodia and filopodia, respectively. The enormous versatility of the intracellular actions of Rho, Rac, and Cdc42 highlights their ability to control a majority of important cellular processes, including cell proliferation, apoptosis, cell survival, cell polarity, cell adhesion, and membrane trafficking. Therefore, it is not surprising that alteration of either the expression or activation status of different Rho GTPases can lead to different pathologies. This is especially true for tumorigenesis because a large number of recent studies have implicated Rho, Rac, and Cdc42 expression in malignant transformation of mammalian cells as well as the progression and dissemination of various tumors. A majority of these studies focused on breast [Tang et al., 2008], ovarian [Cheng et al., 2009] and hepatocellular [Grise et al., 2009] cancers. In contrast, the involvement of Rho GTPases in colorectal cancer, the second most lethal neoplasia worldwide, is not well understood [Jemal et al., 2006]. Here, we provide an overview of the recent findings concerning the role that the three most studied members of Rho GTPase family, Rho, Rac, and Cdc42, play in the development of colorectal cancer as well as the molecular mechanisms that mediate Rho-dependent cell transformation. EXPRESSION AND REGULATION OF Rho GTPases Rho GTPase members are regulated by both protein regulator signaling and cell surface receptors. They also play a pivotal role in gene expression, cell proliferation, apoptosis, and other various Journal of Cellular Biochemistry PROSPECTS Journal of Cellular Biochemistry 113:2549–2559 (2012) 2549 Grant sponsor: CNPq; Grant number: 573806/2008-0; Grant sponsor: FAPERJ; Grant number: E26/170.026/2008; Grant sponsor: Ministerio da Saude-Brazil. *Correspondence to: Jose ´ Andre ´s Morgado-Dı ´az, Grupo de Biologia Estrutural, Divisa ˜ o de Biologia Celular, Centro de Pesquisas, Instituto Nacional de Ca ˆncer–INCa, Rio de Janeiro 2231050, Brazil. E-mail: jmorgado@inca.gov.br Manuscript Received: 15 March 2012; Manuscript Accepted: 20 March 2012 Accepted manuscript online in Wiley Online Library (wileyonlinelibrary.com): 30 March 2012 DOI 10.1002/jcb.24153  ß 2012 Wiley Periodicals, Inc.