The Small GTPase RAC1B: A Potent Negative Regulator of-and Useful Tool to Study-TGFβ Signaling

Simple Summary Transforming growth factor β (TGFβ) promotes pancreatic ductal adenocarcinoma (PDAC) primarily through its non-canonical (non-Smad) signaling arms, including signaling by the small GTPase RAC1. The human RAC1 gene also encodes for another protein, designated RAC1B, but whether this isoform also interacts with TGFβ signaling has remained unknown. In a series of studies in PDAC-derived cells, we found that RAC1B also cross-talks with TGFβ signaling, but unlike RAC1 antagonizes TGFβ-induced responses, i.e., epithelial–mesenchymal transition, through multiple mechanisms. However, rather than being uniformly inhibitory, RAC1B selectively blocks tumor-promoting pathways, while concomitantly allowing tumor-suppressive pathways to proceed. In this review article, we discuss the specific interactions between RAC1B and TGFβ signaling, which occur at multiple levels and include various components of both the canonical Smad and non-Smad pathways. In addition to emerging as a novel tumor suppressor in PDAC, RAC1B turned out to be a useful tool to dissect TGFβ signaling. Abstract RAC1 and its alternatively spliced isoform, RAC1B, are members of the Rho family of GTPases. Both isoforms are involved in the regulation of actin cytoskeleton remodeling, cell motility, cell proliferation, and epithelial–mesenchymal transition (EMT). Compared to RAC1, RAC1B exhibits a number of distinctive features with respect to tissue distribution, downstream signaling and a role in disease conditions like inflammation and cancer. The subcellular locations and interaction partners of RAC1 and RAC1B vary depending on their activation state, which makes RAC1 and RAC1B ideal candidates to establish cross-talk with cancer-associated signaling pathways—for instance, interactions with signaling by transforming growth factor β (TGFβ), a known tumor promoter. Although RAC1 has been found to promote TGFβ-driven tumor progression, recent observations in pancreatic carcinoma cells surprisingly revealed that RAC1B confers anti-oncogenic properties, i.e., through inhibiting TGFβ-induced EMT. Since then, an unexpected array of mechanisms through which RAC1B cross-talks with TGFβ signaling has been demonstrated. However, rather than being uniformly inhibitory, RAC1B interacts with TGFβ signaling in a way that results in the selective blockade of tumor-promoting pathways, while concomitantly allowing tumor-suppressive pathways to proceed. In this review article, we are going to discuss the specific interactions between RAC1B and TGFβ signaling, which occur at multiple levels and include various components such as ligands, receptors, cytosolic mediators, transcription factors, and extracellular inhibitors of TGFβ ligands.