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Review
. 2010 Dec;10(12):842-57.
doi: 10.1038/nrc2960. Epub 2010 Nov 24.

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

Dominico Vigil  1 , Jacqueline Cherfils, Kent L Rossman, Channing J Der
Affiliations
Review

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

Dominico Vigil et al. Nat Rev Cancer. 2010 Dec.

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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Conflict of interest statement

Competing interests statement

The authors declare no competing financial interests.

Figures

Figure 1
Figure 1. GEFs and GAPs are multi-domain proteins
This figure focuses on those GEFs and GAPs where some degree of validation has been accomplished, and parallels those listed Supplementary Tables S1 and S2. A key point of this figure is to emphasize the complex domain topology of GEFs and GAPs. Beyond their shared catalytic domains, there is significant diversity in the structure of GEFs and GAPs for a specific GTPase. This diversity is especially striking for RhoGEFs and RhoGAPs. These flanking domains or motifs are often involved in promoting their activation by upstream signals (e.g., Ras-binding/association domains). The domains include those that promote protein-protein (e.g., Src homology 2 and 3 domains) or protein-lipid interactions, second messenger binding and protein kinase phosphorylation sites. These interactions may facilitate association with specific subcellular membranes or compartments, regulating spatially-restricted GTPase activation. These interactions may also regulate autoregulatory sequences or allosteric regulation of GAP or GEF catalytic activity. Others may influence the effectors utilized by the GTPases. Some contain additional catalytic domains. For example, some RasGEFs also contain DH-PH domains and can activate Rho GTPases. Hence, it is likely that GEFs and GAPs will have GEF/GAP-independent functions and be regulated by GTPase-independent mechanisms. Thus caution should be exercised when using RNA interference to suppress their expression and ascribing cellular activities simply to GTPase activity. For descriptions of domain abbreviations and functions, the reader is referred to the SMART website (see the online links box).
Figure 2
Figure 2. Regulation of RhoGEF activity
For many Dbl family RhoGEFs, N-terminal sequences upstream of the tandem DH-PH domains that catalyze exchange serve as intramolecular, auto-inhibitory sequences. This role is demonstrated by the fact that N-terminal truncations of sequences upstream of the DH-PH domains were responsible for creating the constitutively activated and transforming variants of RhoGEFs identified in transformation or invasion assays. Some RhoGEFs are activated by phosphorylation at an N-terminal motif that relieves the autoinhibitory activity. This is best characterized by Src family protein tyrosine kinase phosphorylation of Vav, and other RhoGEFs, . Other mechanisms of activation involve protein interaction with N-terminal domains, such G alpha 12/13 interaction with the RGS box-containing RhoGEFs (p115-RhoGEF, Larg and PDZ-RhoGEF)–, Ras interaction with the RBD in Tiam1 and APC association with the N-terminus of Asef–. Thus, these mechanisms of upstream activation identify potential avenues for RhoGEF inhibition in cancer. For example, Vav activation in pancreatic and head and neck cancers involves activation by EGFR-mediated phosphorylation and activation. Therefore, inhibitors of EGFR or the intermediate Src family kinases may be one approach for blocking Vav-mediated oncogenesis.
Figure 3
Figure 3. Inhibition of GEFs by Brefeldin A and related molecules
a | The crystallographic structure of Arf-GDP-Sec7 complex inhibited by BFA (modified from). BFA (in red) sneaks in a hydrophobic cavity at the interface between the small G protein Arf (green) and the catalytic domain of its GEF (blue), where it establishes tight hydrophobic and polar contacts with both partners of the complex, . Nature probably selected this low affinity intermediate (>100 mM) because its energy is unbalanced. This unbalance triggers the conformational change that secures GTP-bound Arf to membranes in the unperturbed reaction, but also yields the conditions for the binding of a small molecule inhibitor. b | Interfacial inhibitors trap abortive complexes by binding in (left), or at the periphery of (right), protein-protein interfaces. Molecules that inhibit the Sec7 domain of ArfGEFs: BFA, LM11, SecinH3 and M69. (reproduced from, , , )
See this image and copyright information in PMC

References

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