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The 'invisible hand': regulation of RHO GTPases by RHOGDIs

Nature Reviews Molecular Cell Biology volume 12, pages 493–504 (2011)Cite this article

Subjects

Key Points

  • RHO-specific guanine nucleotide dissociation inhibitors (RHOGDIs) are a family of proteins that have key roles in the regulation of the RHO GTPases. RHOGDIs function as negative regulators of RHO GTPases, extracting them from membranes and preventing their activation.

  • RHOGDIs maintain a stable soluble pool of inactive RHO GTPases in the cytoplasm. Binding to RHOGDIs protects RHO GTPases from degradation.

  • The total levels of the major RHO GTPases are determined by the levels of RHOGDIs in the cell. RHO proteins that are not bound to RHOGDIs or associated with membranes are degraded.

  • Through competition for binding to RHOGDIs, there is crosstalk between RHO GTPases. Changes in the expression of one leads to the displacement of the others from the RHOGDI and results in their degradation.

  • RHOGDIs play a part in shuttling RHO GTPases between different cellular membranes and regulate the delivery and extraction of RHO GTPases to and from their sites of action.

  • The interaction between RHOGDIs and RHO GTPases can be regulated by several different mechanisms. Some regulate the specific displacement of a single RHO GTPase from RHOGDI, whereas others displace all of the RHO GTPases equally.

  • Changes in expression of RHOGDIs have been associated with different types of cancer.

Abstract

The 'invisible hand' is a term originally coined by Adam Smith in The Theory of Moral Sentiments to describe the forces of self-interest, competition and supply and demand that regulate the resources in society. This metaphor continues to be used by economists to describe the self-regulating nature of a market economy. The same metaphor can be used to describe the RHO-specific guanine nucleotide dissociation inhibitor (RHOGDI) family, which operates in the background, as an invisible hand, using similar forces to regulate the RHO GTPase cycle.

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Figure 1: The RHOGDI cycle.
Figure 2: Structure of the RHOGDI–RHO GTPase complex.
Figure 3: Mechanisms of regulation of the RHOGDI–RHO GTPase interaction.

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Acknowledgements

R.G.M. gratefully acknowledges support from the Simmons Scholars Program. E.B. gratefully acknowledges a Fellowship from the city of Nice (to E.B.) and an Allocation INSERM InCa/AVENIR (#R08227AS). K.B. gratefully acknowledges the Kenan Foundation for support and US National Institutes of Health grants GM029860 and HL080166.

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Authors and Affiliations

  1. Department of Cell and Developmental Biology, University of North Carolina at Chapel Hill.,

    Rafael Garcia-Mata & Keith Burridge

  2. Institut National de la Santé et de la Recherche Médicale Avenir Team, U634, Nice Sophia Antipolis University, Nice, 06107, France

    Etienne Boulter

  3. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill.,

    Keith Burridge

  4. McAllister Heart Institute, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Keith Burridge

Authors
  1. Rafael Garcia-Mata
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  2. Etienne Boulter
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  3. Keith Burridge
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Correspondence to Rafael Garcia-Mata or Keith Burridge.

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DATABASES

NCBI Molecular Modeling Database

12765

SOFTWARE

ClustalW

FURTHER INFORMATION

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Glossary

Switch I and switch II

Two regions in RHO GTPases that undergo a conformational change in the active GTP-bound form and provide a platform for the selective interaction with downstream effectors.

Prenylated

Modified by the attachment of an isoprenoid to a carboxy-terminal Cys residue.

Isoprenoid

A compound that is derived from isoprene (2-methyl-1,3-butadiene) molecules linked together in a head-to-tail or a tail-to-tail conformation. These include farnesyl diphosphate or geranylgeranyl diphosphate molecules, which are used in the covalent modification of proteins on Cys residues.

Isoprenylation

Post-translational modification of proteins by the attachment of an isoprenoid to a carboxy-terminal Cys residue. The isoprenoids used, farnesyl diphosphate or geranylgeranyl diphosphate, are derived from the same biochemical pathway that produces cholesterol.

Geranylgeranyl

A 20-carbon isoprenoid precursor to geranylgeranylated proteins. The source of the geranylgeranyl group is geranylgeranyl pyrophosphate, an intermediate in the hydroxy-methylglutaryl CoA reductase pathway that is used by organisms in the biosynthesis of terpenes and terpenoids.

Immunoglobulin-like fold

A type of protein domain that consists of a two-layer sandwich of between seven and nine antiparallel β-strands arranged in two β-sheets.

Steric hindrances

Obstructions that occur when the size of groups within a molecule prevents chemical reactions that are observed in related smaller molecules.

Isomerization

The process by which one molecule is transformed into another molecule that has exactly the same molecular formula but a different structure.

Lipid raft

A membrane microdomain that is enriched in cholesterol, sphingolipids and lipid-modified proteins, such as glycosyl phosphatidylinositol-linked proteins and palmitoylated proteins. These microdomains often function as platforms for signalling events.

DBL homology domain

A domain of ∼200 amino acids that has been shown to encode guanine nucleotide exchange factor activity towards many specific RHO family members.

Pleckstrin homology domain

A protein domain of ∼120 amino acids that is found in a wide range of proteins involved in intracellular signalling. Frequently, these domains bind cell membranes by interacting with acidic phospholipids, such as phosphoinositides.

Lamellae

Flat, sheet-like protrusions at the edge of the cell. A fan-shaped lamella is a prominent feature identifying the leading edge of a cell undergoing locomotion on a flat surface. Actin networks are the principal structures within these lamellae.

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Garcia-Mata, R., Boulter, E. & Burridge, K. The 'invisible hand': regulation of RHO GTPases by RHOGDIs. Nat Rev Mol Cell Biol 12, 493–504 (2011). https://doi.org/10.1038/nrm3153

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