The on-off relationship of Rho and Rac during integrin-mediated adhesion and cell migration - PubMed (original) (raw)

Review

The on-off relationship of Rho and Rac during integrin-mediated adhesion and cell migration

Campbell D Lawson et al. Small GTPases. 2014.

Abstract

Rho GTPases play an essential role in regulating cell spreading, adhesion, and migration downstream of integrin engagement with the extracellular matrix. In this review, we focus on RhoA and Rac1--2 Rho GTPases that are required for efficient adhesion and migration--and describe how specific guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) regulate the extensive crosstalk that exists between them. In particular, we assess the role of GEFs and GAPs in light of recent, unexpected evidence concerning the spatiotemporal relationship between RhoA and Rac1 at the leading edge of migrating cells. Force is increasingly recognized as a key regulator of cell adhesion and we highlight the role of GEFs and GAPs in mechanotransduction, before debating the controversial role of tension in focal adhesion maturation.

Keywords: GAP; GEF; Rac1; Rho GTPase; RhoA; adhesion; integrin; mechanotransduction; migration.

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Figures

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Figure 1. Regulation of Rho GTPase activity by GEFs, GAPs, and GDIs. At the membrane, inactive, GDP-bound Rho GTPases can be activated by GEFs, which catalyze the exchange of GDP for GTP. Once GTP-bound, Rho GTPases can bind to a variety of downstream effectors and elicit diverse responses. GAPs catalyze the GTPase-dependent hydrolysis of GTP back into GDP, thus inactivating Rho proteins. In the cytosol, Rho GTPases are bound by GDIs which prevent nucleotide exchange and bury the prenylated C-terminus, thus preventing degradation.

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Figure 2. Crosstalk between RhoA and Rac1 in migrating cells. At the leading edge of migrating cells, RhoA can be activated by GEFs such as p190RhoGEF, GEF-H1, LARG, and Syx. At the cell rear, RhoA can restrict Rac1 activity via FilGAP and by negatively regulating the localization of β-Pix. RhoA-stimulated mDia activity may contribute to the subsequent increase in Rac1 activity at the leading edge, possibly by activating Src-dependent GEFs such as Tiam1 and DOCK180. Rac1 can inhibit RhoA via p190RhoGAP and the decrease in RhoA activity may further activate Rac1 by preventing FilGAP activation and by relieving the inhibition of β-Pix. The association of inactive RhoA with RhoGDI could also increase Rac1 activity as a result of the competitive binding of these 2 GTPases to GDI. See text for further details.

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