The Dual Function of RhoGDI2 in Immunity and Cancer

Abstract

RhoGDI2 is a guanine nucleotide dissociation inhibitor (GDI) specific for the Rho family of small GTPases. It is highly expressed in hematopoietic cells but is also present in a large array of other cell types. RhoGDI2 has been implicated in multiple human cancers and immunity regulation, where it can display a dual role. Despite its involvement in various biological processes, we still do not have a clear understanding of its mechanistic functions. This review sheds a light on the dual opposite role of RhoGDI2 in cancer, highlights its underappreciated role in immunity and proposes ways to explain its intricate regulatory functions.

Hyperglycemic Stress Induces Expression, Degradation, and Nuclear Association of Rho GDP Dissociation Inhibitor 2 (RhoGDIβ) in Pancreatic β-Cells

“…From a mechanistic standpoint, the GEFs facilitate the activation of G proteins by promoting the release of GDP to enable GTP binding. The GAPs catalyze the hydrolysis of GTP-bound G proteins to GDP, resulting in the inactivation of the candidate G proteins [8,[10][11][12]. The functional roles of the GDIs include the sequestration of G proteins in their GDP-bound conformation, thereby preventing their functional activation by GEFs.…”

“…The functional roles of the GDIs include the sequestration of G proteins in their GDP-bound conformation, thereby preventing their functional activation by GEFs. In this context, the G protein activation-deactivation (also referred to as the GTPase hydrolytic cycle) mediated by these proteins/factors is highly complex given the fact that many GEFs (~82) and GAPs (~70) are expressed in 2 of 13 mammalian cells [11,13]. Interestingly, despite such a large abundance of GEFs and GAPs, only three GDIs, namely, RhoGDIα, RhoGDIβ, and RhoGDIγ, are expressed in mammalian cells.…”

“…RhoGDIβ (also referred to as RhoGDI2, LyGDI, D4-GDI, and ARHGDIB) has been shown to be expressed in hematopoietic cells. RhoGDIγ (also known as RhoGDI3) has been shown to be expressed predominantly in the brain, pancreas, lungs, kidney, and testis [9,11,[13][14][15]. Recent investigations by Ahmad Mokhtar and coworkers suggested that RhoGDIα and RhoGDIβ bind and regulate functions of the Rho and Rac subfamilies of G proteins, whereas RhoGDIγ exhibits a wider specificity of regulation of typical G proteins such as Rho, Rac, and Cdc42, as well as some atypical G proteins such as Wrch2/RhoV, Rnd2, Miro2, and RhoH [13].…”

“…In the context of functional roles of RhoGDIs in the regulation of cellular events leading to cellular dysfunction, a growing body of evidence implicates RhoGDIβ in the pathology of various forms of cancers. Interestingly, the expression of RhoGDIβ has been reported to either increase or decrease in different forms of cancer [11]. RhoGDIβ has also been shown to exert roles in several cellular functions, including actin cytoskeletal organization, immune response, vascular remodeling, and cellular apoptosis [11,14].…”

“…Interestingly, the expression of RhoGDIβ has been reported to either increase or decrease in different forms of cancer [11]. RhoGDIβ has also been shown to exert roles in several cellular functions, including actin cytoskeletal organization, immune response, vascular remodeling, and cellular apoptosis [11,14]. From a mechanistic standpoint, earlier studies have reported the caspase-3 (or a caspase-3-like protease)-mediated cleavage of RhoGDIβ at Asp19, leading to the translocation of the truncated form of RhoGDIβ to the nucleus for the propagation of signals necessary for cell apoptosis [20][21][22][23].…”