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.
Highlights
RAC1B is a member of the Rho family of small GTPases and, like RAC1, is a product of the RAC1 gene
When compared with RAC1 and RAC1-GV12, RAC1B binds with much lower affinity or not at all to many common effectors of Rho GTPases, e.g., RHO-GDP dissociation inhibitor (RHO-GDI), GIT-1, and IQGAP, but it does display enhanced binding to proteins involved in transcriptional regulation, cell-cell adhesion, and motility, such as SmgGDS, an atypical guanine nucleotide exchange factor (GEF) with multiple armadillo repeats, RACK1, a scaffolding protein involved in key signaling pathways, and p120(ctn) [21]
Exposure of murine mammary epithelial cells to matrix metalloproteinase-3 (MMP3) induces the expression of Rac1b, which translocates to the cell membrane to promote an increase in cellular reactive oxygen species (ROS) which in turn stimulate the expression of
Summary
RAC1B is a member of the Rho family of small GTPases and, like RAC1, is a product of the RAC1 gene. The majority of data on this RAC-related isoform have been gained from tumor cell models and these strongly support a role of RAC1B in cancer as well as in biological processes that either predispose to cancer like chronic inflammation or initiate its early development. The aim of this review is to serve as a comprehensive manual allowing the interested reader to quickly look up specific aspects of RAC1B biochemistry, cellular functions, signaling interactions, and pharmacological targeting. We summarize available evidence for its emerging role as a prognostic marker in specific tumor entities
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