Editors' ChoiceGTPases

Can Rho Regulate Its Regulator?

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Science Signaling  06 Jul 2010:
Vol. 3, Issue 129, pp. ec208
DOI: 10.1126/scisignal.3129ec208

Studies by Chen et al. of the guanine nucleotide exchange factor (GEF) PRG (PDZ-RhoGEF) indicate that it may participate in a more complex regulatory process than previously anticipated. PRG is a GEF for the small guanosine triphosphatase Rho, which has broad regulatory roles influencing cell motility, structure of the cytoskeleton, cell division, transcription, and other processes. GEFs promote exchange of guanosine diphosphate (GDP) for guanosine triphosphate (GTP) and thus promote activation of small GTPases. As expected for a GEF, PRG bound to nucleotide-free RhoA, but Chen et al. noted that it actually bound more strongly to RhoA in its active form (that is, RhoA bound to a nonhydrolyzable analog of GTP). By analyzing fragments of PRG and solving the crystal structure of a fragment of PRG bound to activated RhoA, the authors determined that PRG bound active Rho through its pleckstrin homology (PH) domain in a molecular interaction similar to that of RhoA with two of its effector proteins. The regions of PRG that bound to activated RhoA did not overlap with those that bind nucleotide-free RhoA to promote the exchange reaction. Furthermore, PRG could be isolated in a ternary complex bound to both forms of RhoA at the same time. It is not yet known how these regulatory interactions might be coordinated, but the authors offer stimulating suggestions: Activated RhoA might provide positive or negative feedback control of the GEF activity of PRG, as the small GTPase Ras does for its GEF SOS (Son of Sevenless). Interaction with active RhoA could also be a mechanism to localize PRG to the plasma membrane. PRG belongs to a family of GEFs that also contain an RGS (regulator of G protein signaling) domain, and PRG’s RGS domain can interact with Gα12 and Gα13, α subunits of receptor-activated heterotrimeric guanine nucleotide–binding proteins (G proteins), providing another means of controlled translocation to the plasma membrane. The dual binding sites in PRG could allow PRG localized by binding to active RhoA to further activate free RhoA in a feed-forward mechanism.

Z. Chen, F. Medina, M.-y. Liu, C. Thomas, S. R. Sprang, P.C. Sternweis, Activated RhoA binds to the pleckstrin homology (PH) domain of PDZ-RhoGEF, a potential site for autoregulation. J. Biol. Chem. 285, 21070–21081 (2010). [Abstract] [Full Text]

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