A role for Rac in Tiaml-induced membrane ruffling and invasion

RHO-LIKE GTPases have been implicated in the regulation of the actin cytoskeleton which controls the morphology, adhesion and motility of cells1-3. Like Ras proteins, they become activated when bound GDP is exchanged for GTP, a process catalysed by GDP-dissociation stimulator (GDS) proteins4. Several GDS proteins specific for Rho-like GTPases have been identified5-8. Most of these contain a conserved catalytic domain, the DBL-homology (DH) domain9, and activate Cdc42 or Rho but not Rac5-8. We have isolated the invasion-inducing Tiaml gene, which also encodes a protein with a DH domain10. Here we show that Tiaml is a GDS protein for Rho-like GTPases in vitro. In fibroblasts, Tiaml induces a similar phenotype as constitutively activated (Vll)Racl, including membrane ruffling, and this is inhibited by dominant negative (N17)Racl. Moreover, T-lymphoma cells expressing V12Racl become invasive, indicating that the Tiaml-Rae signalling pathway could be operating in the invasion and metastasis of tumour cells.