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  • Review Article
  • Published:

Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?

Nature Reviews Cancer volume 10, pages 842–857 (2010)Cite this article

Subjects

Key Points

  • There is increasing evidence that the aberrant activity of numerous members of the Ras superfamily of small GTPases contributes to cancer growth, invasion and metastasis.

  • Unlike the frequent direct mutational activation of the three Ras proteins (which occurs in ∼33% of human cancers), other Ras superfamily GTPases are deregulated by indirect mechanisms, commonly involving the altered expression or activity of their regulatory proteins.

  • Guanine nucleotide exchange factors (GEFs) and GTPase-activating proteins (GAPs) that control the GDP–GTP cycling of specific members of the Ras superfamily have been shown to contribute to cancer by either promoting or suppressing tumour progression and growth.

  • GEFs and GAPs are deregulated in cancer by somatic mutation, changes in gene expression and through post-translational mechanisms owing to aberrant signalling caused by alterations in upstream oncogene or tumour suppressor function.

  • Although GEFs and GAPs are not considered classically druggable targets, there is growing evidence that supports the feasibility of targeting them. For example, nature has provided examples (such as brefeldin A) that provide proof-of-principle of GEF and GAP druggability.

  • The multi-domain structures of GEFs and GAPs contribute to their regulation by diverse signalling mechanisms and might also identify therapeutic approaches for pharmacological regulation of GEF and GAP activity in cancer.

Abstract

There is now considerable and increasing evidence for a causal role for aberrant activity of the Ras superfamily of small GTPases in human cancers. These GTPases function as GDP–GTP-regulated binary switches that control many fundamental cellular processes. A common mechanism of GTPase deregulation in cancer is the deregulated expression and/or activity of their regulatory proteins, guanine nucleotide exchange factors (GEFs) that promote formation of the active GTP-bound state and GTPase-activating proteins (GAPs) that return the GTPase to its GDP-bound inactive state. In this Review, we assess the association of GEFs and GAPs with cancer and their druggability for cancer therapeutics.

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Figure 1: GEFs and GAPs are multi-domain proteins.
Figure 2: Candidate anti-Ras inhibitors.
Figure 3: Regulators and effectors of Ras.
Figure 4: Regulation of RhoGEF activity.
Figure 5: Inhibition of GEFs by brefeldin A and related molecules.
Figure 6: Signalling networks regulated by Ras and Rho family GTPases in cancer.

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Acknowledgements

The authors' research on GEFs and GAPs is supported in part by grants number CA042978, CA129610, CA127152, CA67771 and CA106991 from the US National Institutes of Health (C.J.D.), from the American Cancer Society (D.V. and K.L.R.), and from the Centre National de la Recherche Scientifique, France, (J.C.), and by grants from the Association pour la Recherche Contre le Cancer, France, (J.C.) and the Agence Nationale de la Recherche, France (J.C.). The authors thank L. DeGraffenreid for outstanding assistance in the preparation of this manuscript.

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

    Dominico Vigil, Kent L. Rossman & Channing J. Der

  2. Laboratoire d'Enzymologie et Biochimie Structurales, Centre National de la Recherche Scientifique (CNRS), avenue de la Terrasse, 91198, Gif sur Yvette Cedex, France

    Jacqueline Cherfils

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Glossary

Ras GTPases

Key regulators of extracellular signal-regulated cytoplasmic signalling networks that control cell growth, survival and differentiation.

Rho

This subfamily of Ras GTPases shares similar roles in signal transduction to Ras GTPases and is best-characterized for the regulation of actin cytoskeletal organization and cell shape, movement and polarity.

Rab

This subfamily of Ras GTPases regulate membrane trafficking and intracellular transport.

Arf

This subfamily of Ras GTPases regulate membrane trafficking and intracellular transport.

Ran

This Ras GTPase regulates nucleocytoplasmic transport of macromolecules and the organization of the spindle apparatus during mitosis.

Noonan syndrome

This syndrome is characterized by short stature, characteristic facies, learning problems and a predisposition to develop leukaemia and other cancers, including myeloproliferative disease and neuroblastoma.

CDC25 homology domain

RasGEF catalytic domain, named after the first protein it was identified in: CDC25 in Saccharomyces cerevisiae.

Matrigel

The trade name for a gelatinous protein mixture that is secreted by mouse tumour cells. It resembles the complex extracellular environment found in many tissues and is commonly used as a three-dimensional matrix substrate for cell culture-based in vitro migration and invasion assays.

CAAX motif

C-terminal tetrapeptide sequence comprised of a cysteine, followed by two aliphatic amino acids and a terminal X residue that dictates specificity for farnesyltransferase or geranylgeranyltransferase-I catalysed addition of a C15 farnesyl or C20 geranylgeranyl isoprenoid lipid.

PAK

A group of six structurally similar human serine/threonine kinases that can function as effectors of Rac (PAK1–3) or CDC42 (PAK1–6).

Organotypic

Resembling an organ in vivo, either morphologically or functionally, or both.

Dbl homology (DH) domain

The RhoGEF catalytic domain, named after the first protein it was identified in, the Dbl protein encoded by a transforming gene identified from an NIH 3T3 focus formation assay using genomic DNA from a human diffuse B cell lymphoma.

Pleckstrin homology (PH) domain

A sequence of approximately 100 amino acids that is present in many signalling molecules and that commonly binds to phospholipids and proteins.

Philadelphia chromosome

The chromosome abnormality that causes chronic myeloid leukaemia, formed by a translocation between chromosomes 9 and 22, causing formation of the chimeric BCR–ABL1 tyrosine kinase.

Alternative splicing

A mechanism by which different forms of mature mRNAs are generated from the same gene, leading to the production of more than one related protein or isoform.

Invadopodia

Actin-rich subcellular protrusions with associated proteases used by carcinoma cells to degrade the extracellular matrix to promote invasion.

Farnesyltransferase

One of three human prenyltransferase enzymes, catalyses addition of a 15-carbon farnesyl group to proteins terminating with a CAAX tetrapeptide motif at the carboxyl terminus of a subset of Ras and Rho family GTPases.

Neurofibromatosis type 1

Patients with this autosomal dominant familial syndrome are at increased risk of developing tumours of the peripheral and central nervous system, including neurofibromas, plexiform neurofibromas, malignant peripheral nerve sheath tumours and low-grade gliomas.

mTOR

A serine/threonine kinase that regulates cell growth, cell proliferation, cell motility, cell survival, protein synthesis and gene transcription, autophagy and angiogenesis.

StAR-related lipid transfer (START) domain

A ∼200 amino acid motif initially identified as a lipid-binding domain.

Sterile α-motif

SAM. A ∼70 amino acid domain involved in protein–protein interactions that is found in a wide variety of proteins involved in many biological processes.

Druggability

The likelihood of being able to modulate the activity of a target protein with a small-molecule drug.

Sec7 domain

ArfGEF catalytic domain, named after the first protein that it was identified in S. cerevisiae SEC7.

Aptamer

A double-stranded DNA, single-stranded RNA or peptide that binds to specific molecular targets, such as a protein or metabolite. Aptamers are usually selected from large libraries of synthesized molecules.

Fluorescence polarization

A technique specially applied to study molecular interactions. When fluorescent molecules in solution are excited with plane-polarized light, they will rotate and tumble, and the planes into which light is emitted can be very different from the plane used for initial excitation.

RGS domain

Functions in a similar manner to GTPase-activating proteins by accelerating the intrinsic GTP hydrolysis activity of heterotrimeric Gα subunits, causing inactivation of GPCR signalling.

C1 zinc finger domain

An ∼50 amino acid phospholipid binding domain. It typically binds membrane-bound phorbol esters or diacylglycerol to promote membrane localization.

ROCK

A serine/threonine kinase that is an effector of RHOA and RHOC and phosphorylates proteins that regulate actin stress fibre formation and focal adhesion assembly.

MRCK

Serine/threonine kinases that preferentially bind to activated CDC42 and phosphorylate proteins that regulate actin reorganization.

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Vigil, D., Cherfils, J., Rossman, K. et al. Ras superfamily GEFs and GAPs: validated and tractable targets for cancer therapy?. Nat Rev Cancer 10, 842–857 (2010). https://doi.org/10.1038/nrc2960

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