Deregulation of Rho GTPases in cancer

Abstract

In vitro and in vivo studies and evidence from human tumors have long implicated Rho GTPase signaling in the formation and dissemination of a range of cancers. Recently next generation sequencing has identified direct mutations of Rho GTPases in human cancers. Moreover, the effects of ablating genes encoding Rho GTPases and their regulators in mouse models, or through pharmacological inhibition, strongly suggests that targeting Rho GTPase signaling could constitute an effective treatment. In this review we will explore the various ways in which Rho signaling can be deregulated in human cancers.

Keywords: GAPs; GDI; GEFs; Rho GTPases mutations; cancer; tumorigenesis.

Figure 1.

The Rho GTPase cycle GTPase regulation occurs in a number of distinct stages. Guanine nucleotide exchange factors (GEFs) are able to bind to inactive GTPases, displacing the bound GDP, which is then replaced by GTP from the cytoplasm. In their active form Rho GTPases bind to a wide variety of effectors, mediating a large number of cellular processes, including migration, cell-cell adhesion, transcription and proliferation. GEFs also may act to direct signaling by scaffolding particular effectors. To end signaling, GTPase activating proteins (GAPs) bind to the GTPase and enhance their weak intrinsic GTPase activity. Bound GTP is converted to GDP, changing the conformation of the GTPase and rendering it unable to bind effector proteins. Inactive GTPases are mainly found in the cytoplasm, where they can be degraded, or stabilised by binding to Rho GDIs, which act as molecular chaperones and prevent activation by sequestering the GTPases away from GEFs.

Figure 2.

Rho GTPase signaling can be deregulated in cancer by a wide range of mechanisms. (1) Evidence is emerging of many direct mutations of GTPases, such as the Rac1 P29S mutation which is a novel driver in melanoma. (2) GEFs are found overexpressed in many different cancer types, consistent with aberrant Rho GTPase signaling driving transformation and oncogenic progression. (3) Negative regulators of Rho GTPases, such as Rho GAPs and Rho GDIs, have been shown to be tumour suppressors, and lost in human cancers. (4) GTPases are often found to be overexpressed in human cancers, where they drive a variety of oncogenic processes. (5) Post-translational modifications of GTPases, such as changes in ubiquitylation or sumoylation, can alter their signaling. (6) The Rac1b splice form of Rac1 is found in multiple cancers including breast, colon and lung.