The diverse roles of Rac signaling in tumorigenesis

Abstract

Rac is a member of the Rho family of small GTPases, which act as molecular switches to control a wide array of cellular functions. In particular, Rac signaling has been implicated in the control of cell-cell adhesions, cell-matrix adhesions, cell migration, cell cycle progression and cellular transformation. As a result of its functional diversity, Rac signaling can influence several aspects of tumorigenesis. Consistent with this, in vivo evidence that Rac signaling contributes to tumorigenesis is continuously emerging. Additionally, our understanding of the mechanisms by which Rac signaling is regulated is rapidly expanding and consequently adds to the complexity of how Rac signaling could be modulated during tumorigenesis. Here we review the numerous biological functions and regulatory mechanisms of Rac signaling and discuss how they could influence the different stages of tumorigenesis.

Figure 1

Multiple mechanisms exist to regulate Rac activity. The Rac GTPase cycles between inactive GDP-bound and active GTP-bound states. Rac activation is facilitated by the action of GEFs, which promote GDP dissociation from Rac and allow GTP to bind instead. Through the association with GAPs the intrinsic GTPase activity of Rac is accelerated, thereby inactivating Rac. Through association with RhoGDIs Rac can be sequestered in its inactive state. Activated Rac can also be removed through Ubiquitylation-induced degradation, or it can be maintained following its modification by SUMO.

Figure 2

Schematic representation of epithelial cell-cell adhesions. (A) Typical organization of epithelial cell-cell junctions and apical-basal polarity. The different types of cell-cell junctions are shown. (B) The main constituents of epithelial adherens junctions (AJ) and tight junctions (TJ).

Figure 3

Schematic representation summarizing how Rac-mediated regulation of cell-cell adhesions may contribute to different stages of tumorigenesis.

Figure 4

Schematic representation summarizing how Rac-mediated regulation of cell migration and invasion may contribute to tumor metastasis.

Figure 5

Schematic representation of how Rac-mediated regulation of cell proliferation and survival may contribute to tumor growth.

Figure 6

Schematic representation summarizing how Rac-mediated regulation of various important cellular processes may contribute to multiple stages of tumorigenesis.