Targeting Rho-GTPases in immune cell migration and inflammation.
Bottom Line: This review describes advances in the development of small-molecule inhibitors aimed at modulating the Rho-GTPase-centric regulatory pathways governing motility, many of which stem from studies of cancer invasiveness.These inhibitors promise the advent of novel treatment options with high selectivity and potency against immune-mediated pathologies.This article is part of a themed section on Cytoskeleton, Extracellular Matrix, Cell Migration, Wound Healing and Related Topics.
Affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Immune Imaging Program, Newtown, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.Show MeSH
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Mentions: Complex and as yet incompletely mapped signalling pathways are responsible for the precise spatiotemporal regulation of cellular actomyosin. The central components of these pathways are small GTPases of the Rho family (Rho-GTPases), notably Rho, Rac and Cdc42 (Hall, 2012). Rho-GTPases govern both contractile and expansive forces required for cell polarization and translocation, and are intricately linked to the overarching regulation of the actomyosin cytoskeleton. Rho-GTPases are found in two inter-convertible states, namely an active GTP-bound state and an inactive GDP-bound state, and can thus function as molecular switches. Exchanges in the GTP- and GDP-state cycle are regulated by guanine nucleotide dissociation inhibitors (GDIs), GTPase-activating proteins (GAPs) and guanine nucleotide exchange factors (GEFs) (Figure 1; Spiering and Hodgson, 2011). GDIs associate with GDP-bound GTPases and prevent these from membrane-association, in effect sequestering them in an inactive sate. GEFs catalyse GDP-to-GTP nucleotide exchange and thereby activate Rho-GTPases. GAPs promote GTP hydrolysis, leading to Rho-GTPase inactivation. In their active state, Rho-GTPases interact with over 60 different target effectors (Etienne-Manneville et al., 2002). Despite the number of potential binding partners, active Rho-GTPases interact with specific effectors at any one time. Interactions between Rho-GTPases and their effectors trigger distinct changes in the actomyosin cytoskeleton. The Rho-GTPases can mediate signalling cascades that result in actin polymerization and network formation, as well as regulate myosin contractility. A model of the intricate pathways downstream of Rho-GTPase activation and the degree of crosstalk between the different Rho-GTPases is illustrated in Figure 2.
Affiliation: Centenary Institute of Cancer Medicine and Cell Biology, Immune Imaging Program, Newtown, NSW, Australia; Sydney Medical School, The University of Sydney, Sydney, NSW, Australia.