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  • Review Article
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GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors

Nature Reviews Molecular Cell Biology volume 6, pages 167–180 (2005)Cite this article

Key Points

  • Human Rho GTPases (of which there are 22 members) comprise a main branch of the Ras superfamily of small GTPases and GDP/GTP-regulated molecular switches. Rho GTPases are activated by the direct engagement of guanine nucleotide-exchange factors (GEFs), which catalyse the ejection of GTPase-bound GDP and the loading of GTP. In humans, the ∼70 Dbl-family proteins comprise the largest group of Rho GEFs.

  • Dbl-family proteins are characterized by a catalytic Dbl homology (DH) domain that is immediately adjacent to a regulatory C-terminal pleckstrin homology (PH) domain. DH domains engage the flexible switch regions of GTPases, which leads to their remodelling and the exchange of nucleotides. PH domains assist in this process by less well understood, and more varied, mechanisms.

  • In most scenarios, PH domains are thought to bind weakly to phosphoinositides to facilitate GDP/GTP exchange. The binding of phosphoinositides has been proposed to facilitate this exchange by causing allosteric changes within the DH–PH array. However, it is more likely that phosphoinositide binding functions to guide the precise subcellular localization of Dbl proteins, and to orientate DH–PH arrays at lipid bilayers to promote the productive engagement of membrane-bound GTPases.

  • Dbl proteins function to integrate diverse extracellular stimuli — for example, signals from heterotrimeric G-protein-coupled- or tyrosine-kinase-associated receptors that control the spatio-temporal activation of Rho GTPases. Regulatory mechanisms include the intramolecular autoinhibition of Dbl proteins, which can be relieved by various inputs — most notably, phosphorylation. It is likely that the flux of phosphoinositide levels regulates the exchange activity of Dbl proteins.

  • In addition to Dbl proteins, Dock-family human proteins (11 members), as well as bacterial proteins, expand the diversity of proteins that function as GEFs and activators of Rho GTPases.

  • The contribution of aberrant Rho-GTPase function to human disease is supported by the association of mutated Dbl-family proteins with cancer, developmental and neurological disorders. Furthermore, viral and bacterial pathogens manipulate Rho GEFs to facilitate their invasion and pathogenicity of human cells.

Abstract

Guanine nucleotide-exchange factors (GEFs) are directly responsible for the activation of Rho-family GTPases in response to diverse extracellular stimuli, and ultimately regulate numerous cellular responses such as proliferation, differentiation and movement. With 69 distinct homologues, Dbl-related GEFs represent the largest family of direct activators of Rho GTPases in humans, and they activate Rho GTPases within particular spatio-temporal contexts. The failure to do so can have significant consequences and is reflected in the aberrant function of Dbl-family GEFs in some human diseases.

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Figure 1: Regulating Rho-GTPase activity.
Figure 2: The Dbl family.
Figure 3: Three-dimensional structures of DH–PH domains.
Figure 4: Key interactions viewed within the structure of Dbs–Cdc42.
Figure 5: Model of PH-domain-assisted guanine nucleotide exchange.
Figure 6: Rho GEFs as signalling nodes.
Figure 7: Mutation of Rho GEFs in human diseases.

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Acknowledgements

We would like to apologize for not being able to cite original work of many colleagues due to space constraints. Our studies are supported by grants to C.J.D. and to J.S from the National Institutes of Health. K.L.R. was supported by a fellowship from the National Cancer Institute.

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Authors and Affiliations

  1. Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Kent L. Rossman, Channing J. Der & John Sondek

  2. Department of Pharmacology, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    Kent L. Rossman, Channing J. Der & John Sondek

  3. Department of Biochemistry and Biophysics, University of North Carolina at Chapel Hill, Chapel Hill, 27599, North Carolina, USA

    John Sondek

Authors
  1. Kent L. Rossman
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  2. Channing J. Der
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Correspondence to Channing J. Der or John Sondek.

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DATABASES

Entrez

SopE

SopE2

Interpro

Bar domain

DH domain

PH domain

Saccharomyces genome database

Cdc24

Cdc25

Swiss-Prot

Cdc42

Dbl

Dbs

ITSN-L

LARG

Miro1

p115-RhoGEF

PDZ-RhoGEF

α-Pix

β-Pix

Rac1

Ras

Rcc1

RhoA

RhoBTB1

RhoD

RhoE

RhoF

RhoG

RhoH

RhoV

Sos1

Tara

Tiam1

Trio

Vav1

FURTHER INFORMATION

SMART database

Protein Data Bank

Glossary

G-PROTEIN-COUPLED RECEPTOR

A seven-helix membrane-spanning cell-surface receptor that signals through heterotrimeric GTP-binding and -hydrolysing G proteins to stimulate or inhibit the activity of a downstream enzyme.

PHAGOCYTOSIS

An actin-dependent process by which cells engulf external particulate material by extension and fusion of pseudopods.

CYTOKINESIS

The separation of a cell into two, which is marked by ingression of the cleavage 'furrow' between two segregated masses of genomic DNA.

PLECKSTRIN HOMOLOGY (PH) DOMAIN

A sequence of ∼100 amino acids that is present in many signalling molecules and that binds to lipid products of phosphatidylinositol 3-kinase. Pleckstrin is a protein of unknown function that was originally identified in platelets. It is a principal substrate of protein kinase C.

SWITCH REGIONS

Regions of nucleotide-binding proteins that have different conformations in the triphosphate-bound, compared to the diphosphate-bound, state.

α-HELIX

An element of protein secondary structure in which hydrogen bonds that lie along the backbone of a single polypeptide cause the chain to form a right-handed helix.

310 HELIX

A tighter, less stable helix than the α-helix, with three residues per turn, which form hydrogen-bonded loops of 10 atoms.

HOMOLOGY MODELLING

Prediction of the tertiary structure of an unknown protein using a known three-dimensional structure of a homologous protein.

CLEAVAGE FURROW

An invagination of the plasma membrane in the division plane of an animal cell that contains a contractile ring, and that leads to scission of the daughter cells.

CHEMOTAXIS

A type of migration that is stimulated by a gradient of a chemical stimulant or chemoattractant.

SCAFFOLD

A protein that functions as a support to assemble a multiprotein complex.

SRC-HOMOLOGY-3 (SH3) DOMAIN

A protein module of ∼80 amino acids that is present in a range of proteins and that was first identified in the protein kinase Src. SH3 domains interact with proline-rich sequences that usually contain a PXXXPXR motif (where X is any amino acid).

PDZ DOMAIN

(Postsynaptic-density protein of 95 kDa, Discs large and Zona occludens-1). A region that is present in several scaffolding proteins and that is named after the founding members of this protein family. PDZ domains bind to specific short amino-acid sequences that are found in several proteins at, or outside, junctions.

HETEROTRIMERIC G PROTEIN

A complex of three proteins (Gα, Gβ and Gγ). Whereas Gβ and Gγ form a tight complex, Gα is part of the complex in its inactive, GDP-bound, form but dissociates in its active, GTP-bound, form. Both Gα and Gβγ can transmit downstream signals after activation.

GROWTH CONE

Motile tip of the axon or dendrite of a growing nerve cell, which spreads out into a large cone-shaped appendage.

BUD SITES

Cell-wall sites where the yeast S. cerevisiae undergoes reproduction by initiation of budding.

MATING PROJECTION

A specialized structure that is formed by vegetative S. cerevisiae to initiate polarized cell growth, and to allow polarized mating cells to signal to one another.

DOMINANT NEGATIVE

A defective protein that retains interaction capabilities and so distorts or competes with normal proteins.

EXPRESSION-LIBRARY SCREENS

A genome-wide cloning strategy that uses a biological gain-of-function (for example, uncontrolled growth) to isolate and identify genes with specific cellular activities.

C2 DOMAIN

Better known as Ca2+-dependent phospholipid-binding domains in proteins such as conventional protein kinase C isoforms and synaptotagmin. The C2 domain is another modular signalling domain that can induce membrane–protein, or protein–protein, interactions, after binding several Ca2+ ions. There are C2 domains that do not bind Ca2+ but constitutively bind to a membrane, others that might be involved in Ca2+-independent protein–protein interactions, and some that might bind inositol polyphosphates.

ARMADILLO (ARM) ARRAY

The armadillo repeat is an ∼40-amino-acid-long tandemly repeated sequence motif that was first identified in the Drosophila melanogaster segment polarity gene armadillo.

SQUAMOUS CELL CARCINOMA

A carcinoma that develops from the layers of thin, flat squamous cells of the epithelium.

CALPONIN-HOMOLOGY DOMAIN

A protein domain, which is often found tandemly arrayed, that functions in the binding of actin.

CYTOPATHICITY

The ability of certain viruses to cause degenerative changes in their host cells as a consequence of viral invasion and multiplication. This might include changes in cell morphology, cell lysis, cell death and altered cell–cell interactions.

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Rossman, K., Der, C. & Sondek, J. GEF means go: turning on RHO GTPases with guanine nucleotide-exchange factors. Nat Rev Mol Cell Biol 6, 167–180 (2005). https://doi.org/10.1038/nrm1587

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