Dysregulation of Rho GTPases in Human Cancers

Abstract

Rho GTPases play central roles in numerous cellular processes, including cell motility, cell polarity, and cell cycle progression, by regulating actin cytoskeletal dynamics and cell adhesion. Dysregulation of Rho GTPase signaling is observed in a broad range of human cancers, and is associated with cancer development and malignant phenotypes, including metastasis and chemoresistance. Rho GTPase activity is precisely controlled by guanine nucleotide exchange factors, GTPase-activating proteins, and guanine nucleotide dissociation inhibitors. Recent evidence demonstrates that it is also regulated by post-translational modifications, such as phosphorylation, ubiquitination, and sumoylation. Here, we review the current knowledge on the role of Rho GTPases, and the precise mechanisms controlling their activity in the regulation of cancer progression. In addition, we discuss targeting strategies for the development of new drugs to improve cancer therapy.

Keywords: Rho GTPases; cancer; chemoresistance; metastasis; migration.

Figure 1

Guanosine diphosphate (GDP)-guanosine triphosphate (GTP) exchange cycle of Rho GTPases. Classic Rho GTPases, such as Rho, Rac, and Cdc42 subfamilies, follow GDP/GTP cycling regulated by Rho guanine nucleotide exchange factors (RhoGEFs), Rho GTPase-activating proteins (RhoGAPs), and Rho guanine nucleotide dissociation inhibitors (RhoGDIs). Rnd and RhoBTB subfamilies cannot be accelerated by RhoGAPs. The RhoU/RhoV and RhoD/RhoF subfamilies have high intrinsic GTP/GDP exchange activity.

Figure 2

The regulation of Rho GTPases activation. Most Rho GTPases are regulated by RhoGEFs, RhoGAPs, and RhoGDIs. Rho GTPases are also regulated by post-translational modification, including phosphorylation, sumoylation, and ubiquitination. Post-translational modifications (PTMs) of Rho GTPases regulate their intracellular localization, stability, and ability to signal to downstream effector.