Regulation of Rho GTPases by RhoGDIs in Human Cancers

Abstract

Rho GDP dissociation inhibitors (RhoGDIs) play important roles in various cellular processes, including cell migration, adhesion, and proliferation, by regulating the functions of the Rho GTPase family. Dissociation of Rho GTPases from RhoGDIs is necessary for their spatiotemporal activation and is dynamically regulated by several mechanisms, such as phosphorylation, sumoylation, and protein interaction. The expression of RhoGDIs has changed in many human cancers and become associated with the malignant phenotype, including migration, invasion, metastasis, and resistance to anticancer agents. Here, we review how RhoGDIs control the function of Rho GTPases by regulating their spatiotemporal activity and describe the regulatory mechanisms of the dissociation of Rho GTPases from RhoGDIs. We also discuss the role of RhoGDIs in cancer progression and their potential uses for therapeutic intervention.

Keywords: Rho GTPases; RhoGDI1; RhoGDI2; cancer; metastasis; migration.

Figure 1

The regulation of Rho GTPases by GEPs, GAPs, and GDIs. GEFs bind to GDP-bound RhoGTPases and promotes the exchange of GDP for GTP, thereby activating RhoGTPases. GAPs bind to GTP-bound RhoGTPases and catalyze the exchange of GDP for GTP, thereby inactivating RhoGTPases. The N-terminal domain of RhoGDIs binds to switch I and II domains of RhoGTPases. The C-terminal region of RhoGDIs forms a hydrophobic pocket and binds to prenylated RhoGTPases. Therefore, RhoGDIs can extract RhoGTPases from plasm membrane by binding the isoprenoid moiety and sequester them away in the cytoplasmic compartment.