Signalling Through Small GTPases

Raymond R. Mattingly
Markey Center for Cell Signalling
University of Virginia

The Ras superfamily of small GTPases represents a ubiquitous control mechanism for many eukaryotic cell processes. The GTPase domain is highly conserved between different members of the superfamily and provides the controlling switch mechanism. The regions of the GTPase outside this core domain are highly variable and show induced changes in conformation as the protein changes from GTPbound to GDP-bound configurations. The superfamily can be divided by both sequence and function into a number of subfamilies that control specific cellular activities. For example, Ras proteins control cell growth, Rab proteins direct vesicle fusion, Ran is essential for protein/mRNA import/export into/out of the nucleus, and Rac/Rho proteins organize the actin cytoskeleton.

Damage to these small GTPase switches can have catastrophic consequences for the cell and the organism. Several small GTPases of the Rac/Rho subfamily are direct targets for clostridial cytotoxins. Further, Ras proteins are mutated to a constitutively-active (GTPbound) form in approximately 20% of human cancers. In at least one case, that of occupational exposure to vinyl chloride, a connection has been made through a characteristic activating mutation in Ras (codon 13) and thus to the development of an otherwise-rare hepatic angiosarcoma.

Physiological control of these GTPase switches is exerted through exchange factors that catalyze the conversion to the GTP-bound "on" state, and through GAPs (GTPase-activating proteins) that accelerate the intrinsic rate of GTP hydrolysis and the return to the GDP-bound "off" state. Recent work has identified a new pathway for the activation of Ras through the phosphorylation of an exchange factor called RasGRF. Stimulation of receptors coupled to heterotrimeric G proteins can lead to an increase in the specific activity of Ras-GRF towards Ras. Ras-GRF is activated through a G-beta-delta-stimulated increase in its serine phosphorylation state.