Trends in Cell Biology
Volume 11, Issue 12, 1 December 2001, Pages 471-477
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Review
Rho family proteins: coordinating cell responses

https://doi.org/10.1016/S0962-8924(01)02153-5Get rights and content

Abstract

Rho GTPases hit the headlines several times in 1990–1992: the proteins regulating their GTP–GDP cycle were identified and they were found to be key signal transducers, mediating growth factor-induced changes to the actin cytoskeleton and activating the phagocyte NADPH oxidase. Since then, they have been implicated in numerous cellular processes, from cell migration to cell survival, transcriptional regulation and vesicle trafficking. An explanation for why they affect so many aspects of cell behavior might lie in their ability to interact with a number of downstream targets, so that they can coordinately activate several molecular processes required for a particular cellular response.

Section snippets

1991: Linking Rho family proteins to signaling and the actin cytoskeleton

The first inkling that Rho was not merely a Ras surrogate came when Hugh Paterson, working with Alan Hall, microinjected recombinant RhoA protein into fibroblasts. Since recombinant Ras stimulated DNA synthesis when microinjected into fibroblasts 4, they initially looked for effects of RhoA on DNA synthesis. Hugh soon noticed, however, that RhoA dramatically altered the morphology of Swiss 3T3 fibroblasts and found that this correlated with an increase in actin stress fibers 5. When I started

1991: Linking Rac to the NADPH oxidase

While we were busy testing Rac1 and RhoA for effects on the actin cytoskeleton, two groups purified Rac1 and Rac2 as activators of the phagocytic NADPH oxidase 10, 11. Until recently, this was the only in vitro reconstituted system where the function of a GTPase could be studied, and this has been a very fruitful area for studying the principles of Rac action 12, 13. The NADPH oxidase is activated on phagosomes and generates superoxide to aid in the killing of phagocytosed microorganisms. It is

1991: Identifying regulators of the Rho family

Around 1991 was a key time not only for elucidating the functions of Rho and Rac but also for identifying the three types of regulatory proteins that act on Rho family proteins: the guanine nucleotide dissociation inhibitors (GDIs), guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) (Fig. 3).

Downstream targets – from Rho proteins to the actin cytoskeleton

A seminal contribution to the Rho field was the identification by members of the Louis Lim laboratory of the first Rac/Cdc42 targets – the serine/threonine kinase PAK (p21-activated kinase) and the tyrosine kinase ACK, in 1993/1994 30. This came at a time when the interaction of Ras with Raf had just been discovered 31. A key element to the approach used was the selection of proteins that interacted with GTP-bound but not GDP-bound Rac/Cdc42, based on the knowledge that only GTP-bound proteins

What are the functions of new Rho family proteins and regulators?

Even before the sequence of the human genome was released, we knew there were a lot of Rho genes in mammals. However, genome sequencing has revealed a novel Rho subfamily, the RhoBTB genes, found in Dictyostelium, Drosophila and mammals but not C. elegans 72. RhoBTB proteins have a BTB (Broad-Complex, Tramtrack and Bric à brac) domain C-terminal to the GTPase domain. BTB domains are involved in homomeric and heteromeric interactions with other BTB domains 73. So far, nothing is known of the

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