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Regulating Rho GTPases and their regulators

Nature Reviews Molecular Cell Biology volume 17, pages 496–510 (2016)Cite this article

Subjects

Key Points

  • Rho GTPases regulate a wide range of cellular responses, including changes to the cytoskeleton and cell adhesion. Their activity therefore needs to be precisely controlled to determine which response occurs, depending on the context and stimulus.

  • Most Rho GTPases cycle between an active GTP-bound and an inactive GDP-bound form, a process that is regulated by guanine nucleotide exchange factors (GEFs), GTPase-activating proteins (GAPs) and guanine nucleotide dissociation inhibitors (GDIs). In their GTP-bound form, they interact with a diverse range of different targets to induce cellular responses.

  • In addition to GTP–GDP cycling, Rho GTPases are regulated by a diverse range of post-translational modifications, including phosphorylation, ubiquitylation and sumoylation, which alter their localization, activity and stability.

  • GEFs, GAPs and GDIs are also regulated by post-translational modifications, which in turn affect their activity, stability and ability to form protein complexes. These changes then impinge on where and when Rho GTPases are activated.

  • The spatiotemporal activation of Rho GTPases is coordinated by a complex network of post-translational modifications and protein–protein interactions. This determines which Rho GTPase targets are activated, and hence the cellular outcome.

Abstract

Rho GTPases regulate cytoskeletal and cell adhesion dynamics and thereby coordinate a wide range of cellular processes, including cell migration, cell polarity and cell cycle progression. Most Rho GTPases cycle between a GTP-bound active conformation and a GDP-bound inactive conformation to regulate their ability to activate effector proteins and to elicit cellular responses. However, it has become apparent that Rho GTPases are regulated by post-translational modifications and the formation of specific protein complexes, in addition to GTP–GDP cycling. The canonical regulators of Rho GTPases — guanine nucleotide exchange factors, GTPase-activating proteins and guanine nucleotide dissociation inhibitors — are regulated similarly, creating a complex network of interactions to determine the precise spatiotemporal activation of Rho GTPases.

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Figure 1: Overview of Rho GTPase regulation.
Figure 2: Regulation of Rho GTPases by lipid modifications.
Figure 3: Phosphorylation has diverse effects on Rho GTPase signalling.

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Acknowledgements

The authors are grateful to G. Cantelli and R. Brandão-Haga for helpful discussions and comments on the manuscript. This work was supported by Cancer Research UK (C6620/A15961). R.G.H. was supported by the King's Bioscience Institute and the Guy's and St Thomas' Charity Prize Ph.D. Programme in Biomedical and Translational Science.

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  1. Randall Division of Cell and Molecular Biophysics, King's College London, New Hunt's House, Guy's Campus, London, SE1 1UL, UK

    Richard G. Hodge & Anne J. Ridley

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Correspondence to Anne J. Ridley.

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FURTHER INFORMATION

PhosphoSitePlus

Glossary

Integrins

A family of transmembrane cell adhesion receptors that bind to extracellular matrix ligands and other cell adhesion receptors, and interact intracellularly with cytoskeletal proteins.

Prenylation

The attachment of an isoprenoid group to a carboxy-terminal Cys residue or residues. An isoprenoid is a compound that is derived from 5-carbon isoprene (2-methyl-1,3-butadiene) units, which can be linked together in a head-to-tail or a tail-to-tail conformation and include farnesyl diphosphate or geranylgeranyl diphosphate molecules.

Chaperone protein

A protein that contributes to the folding or unfolding of other proteins, and/or the assembly of multiprotein complexes.

S-palmitoylation

Palmitoylation is the process by which a 16-carbon palmitate group is added to a Cys residue by a palmitoyltransferase enzyme. In most cases, palmitate is attached through reversible thioester linkage (S-palmitoylation).

Actomyosin contractility

A process whereby myosin II filaments interact with and move along anti-parallel actin filaments.

CAAX box

A conserved carboxy-terminal amino acid recognition motif, in which C is Cys, A is an aliphatic amino acid and X is variable. The motif is recognized by prenyltransferases that attach an isoprenoid moiety to the Cys residue.

14-3-3 proteins

14-3-3 proteins are homodimeric proteins that bind to a wide range of intracellular proteins, usually by interacting with phosphorylated Ser or Thr residues.

26S proteasome

A protein complex found in mammalian cells that degrades proteins by proteolysis. Polyubiquitylation is a common signal for proteasome-mediated degradation.

BTB domain

A domain that was identified in 'Broad-complex, Tramtrack and Bric-a-brac' proteins in Drosophila melanogaster and that is usually located in the amino-terminal region of proteins. Originally known as the POZ domain, this motif is found in several virus proteins. Many BTB-domain proteins contain a second protein–protein interaction motif, such as zinc-finger or Kelch motifs.

DBL-homology (DH) domain

A domain of approximately 200 amino acids that induces release of GDP from Rho GTPase family members.

Pleckstrin homology (PH) domain

A domain of approximately 120 amino acids. Some pleckstrin homology domains bind to headgroups of membrane lipids on cellular membranes and recruit intracellular signalling proteins to specific compartments.

WAVE regulatory complex

A 400 kDa protein complex composed of five subunits — WAVE, HSPC300, ABI, NAP1 and PIR121 — that activates the ARP2/3 complex via the VCA domain of WAVE. This initiates the polymerization of branched actin filaments.

RING domain

A Cys-rich tandem zinc-finger domain of 40–60 amino acids, often found in E3 ubiquitin ligases.

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Hodge, R., Ridley, A. Regulating Rho GTPases and their regulators. Nat Rev Mol Cell Biol 17, 496–510 (2016). https://doi.org/10.1038/nrm.2016.67

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