RAC1B: A Rho GTPase with Versatile Functions in Malignant Transformation and Tumor Progression

Abstract

RAC1B is an alternatively spliced isoform of the monomeric GTPase RAC1. It differs from RAC1 by a 19 amino acid in frame insertion, termed exon 3b, resulting in an accelerated GDP/GTP-exchange and an impaired GTP-hydrolysis. Although RAC1B has been ascribed several protumorigenic functions such as cell cycle progression and apoptosis resistance, its role in malignant transformation, and other functions driving tumor progression like epithelial-mesenchymal transition, migration/invasion and metastasis are less clear. Insertion of exon 3b endows RAC1B with specific biochemical properties that, when compared to RAC1, encompass both loss-of-functions and gain-of-functions with respect to the type of upstream activators, downstream targets, and binding partners. In its extreme, this may result in RAC1B and RAC1 acting in an antagonistic fashion in regulating a specific cellular response with RAC1B behaving as an endogenous inhibitor of RAC1. In this review, we strive to provide the reader with a comprehensive overview, rather than critical discussions, on various aspects of RAC1B biology in eukaryotic cells.

Keywords: RAC1; RAC1B; Rho GTPase; cancer; epithelial-mesenchymal transition; proliferation; signaling; survival.

Figure 1

Mechanisms utilized by RAC1B to promote cancer progression.

Figure 2

Differential role of RAC1B in epithelial-mesenchymal transition (EMT). Whether RAC1B stimulates or inhibits EMT depends on the EMT-inducing agent. For instance, MMP3 has been reported to promote EMT and TGF-β1 to inhibit it. The role of EMT induced by other mechanisms, e.g., ionizing radiation, still needs to be determined.

Figure 3

Mechanisms utilized by RAC1B to drive G1/S progression.

Figure 4

Illustration of the predominant involvement of RAC1B in cancer-associated signaling pathways. Green arrows pointing away from RAC1B indicate activation, those pointing toward RAC1B indicate upregulation of expression (MEK1/2) or activation (DVL3). Red lines indicate suppression. For details see text.