# RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression
## Conclusions and Perspectives  
### Is RAC1B Really the Bad Brother of RAC1 in Cancer? The majority of studies available so far demonstrates that RAC1B can promote tumor progression when expressed in a protumoral context, e.g., with activated oncogenes, inactivated tumor suppressor genes, or activated cancer-associated signaling pathways. Its tumorigenic role may be elicited at several levels:  
1. by upstream activators that affect its generation and subcellular localization. For instance, PI3-kinase/AKT signaling promotes RAC1B expression via alternative splicing while Wnt signaling inhibits it. 2. by an increase in RAC1B activation levels due to altered regulation by GEFs and GAPs. 3. by functional interactions with factors that promote malignant progression such as oncogenes (BRAF, KRAS) and tumor suppressor genes (APC), or environmental clues such as MMPs. 4. by shifting the balance of pro- to antitumorigenic signaling pathways. For instance, RAC1B activates tumor-promoting NF\(\kappa\)B and KRAS signaling but inhibits tumor-suppressive TGF-\(\beta\) signaling. 5. by stimulating cancer-promoting processes such as carcinogen/acute inflammation or protecting against cancer such as early mucosal repair, depending on the tissue. Depending on the type and physiological state of the target tissue, RAC1B may also be able to counteract malignant progression:  
1. by promoting early mucosal healing after resolution of intestinal inflammation. by antagonizing TGF-\(\beta\) signaling under conditions where TGF-\(\beta\) promotes malignant progression, i.e., in advanced stages of many carcinomas. Despite the predominant evidence for a tumorigenic role, a clear-cut picture on the role of RAC1B in cancer is still lacking. This is mainly because RAC1B does not seem to be tumorigenic per se. For instance, RAC1B overexpression alone was not sufficient to drive intestinal neoplasia or lung cancer progression [24; 25]. The controversial role is also reflected by contradictory findings with respect to proliferation control. Several studies were unable to demonstrate effects of RAC1B on cell cycle progression or surrogate markers of mitotic activity (_CCND1_ expression/reporter gene activity, BrdU incorporation, Ki67 staining). With respect to EMT, MMP3-induced EMT is promoted by RAC1B, while TGF-\(\beta\)-dependent EMT is inhibited, at least in pancreatic cells. Unfortunately, data on the role of RAC1B in EMT induced by still other agents, e.g., ionizing radiation [74] (see Figure 2), are not available. Likewise, cell migration/invasion is either enhanced or inhibited by RAC1B and whether RAC1B can induce the formation of lamellipodia remains an unresolved issue. These discrepancies may partially be explained by cell or tumor type-specific differences of upstream activators and downstream effectors or by the study design. It should be stressed that many studies were carried out under conditions of ectopic overexpression. Given the usually low protein levels of RAC1B in cells compared to RAC1, ectopically expressed RAC1B may by order of magnitudes exceed those of endogenous RAC1B and it might be speculated that as a result of this unphysiologically high expression the observed effects do not truly reflect those displayed by endogenous RAC1B. In some cellular systems this is further complicated by the ability of RAC1B to inhibit expression and/or activity of RAC1 [35; 59]. In cases where both proteins are expressed and act in an antagonistic fashion on the same cellular response, an increase or decrease of RAC1B (regardless of whether physiological or artificial) would not only change the direct effect of RAC1B on this response but would inevitably decrease or increase, respectively, the inverse effect induced by RAC1. Ignoring the phenomenon of RAC1B functioning as an endogenous inhibitor of RAC1 could eventually lead to an overestimation of the RAC1B effect.