A role for Rac in Tiam1-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 cells. Like Ras proteins, they become activated when bound GDP is exchanged for GTP, a process catalysed by GDP-dissociation stimulator (GDS) proteins. Several GDS proteins specific for Rho-like GTPases have been identified. Most of these contain a conserved catalytic domain, the DBL-homology (DH) domain, and activate Cdc42 or Rho but not Rac. We have isolated the invasion-inducing Tiam1 gene, which also encodes a protein with a DH domain. Here we show that Tiam1 is a GDS protein for Rho-like GTPases in vitro. In fibroblasts, Tiam1 induces a similar phenotype as constitutively activated (V12)Rac1, including membrane ruffling, and this is inhibited by dominant negative (N17)Rac1. Moreover, T-lymphoma cells expressing V12Rac1 become invasive, indicating that the Tiam1-Rac signalling pathway could be operating in the invasion and metastasis of tumour cells.
Michiels
F
F
The Netherlands Cancer Institute, Division of Cell Biology, Amsterdam.
Habets
G G
GG
Stam
J C
JC
van der Kammen
R A
RA
Collard
J G
JG
D016475:3T3 Cells; D000818:Animals; D002460:Cell Line; D002462:Cell Membrane / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D005347:Fibroblasts / Q000502:physiology; D020558:GTP Phosphohydrolases / Q000502:physiology; D019204:GTP-Binding Proteins / Q000502:physiology*; D005982:Glutathione Transferase / Q000378:metabolism; D020662:Guanine Nucleotide Exchange Factors; D016244:Guanosine 5'-O-(3-Thiotriphosphate) / Q000502:physiology; D006153:Guanosine Diphosphate / Q000502:physiology; D051379:Mice; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D011506:Proteins / Q000502:physiology*; D011993:Recombinant Fusion Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; D014162:Transfection; D014407:Tumor Cells, Cultured; D020744:rac GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein
D020662:Guanine Nucleotide Exchange Factors; D011506:Proteins; D011993:Recombinant Fusion Proteins; D000075684:T-Lymphoma Invasion and Metastasis-inducing Protein 1; C513260:Tiam1 protein, mouse; D006153:Guanosine Diphosphate; D016244:Guanosine 5'-O-(3-Thiotriphosphate); D005982:Glutathione Transferase; D020558:GTP Phosphohydrolases; D019204:GTP-Binding Proteins; D020744:rac GTP-Binding Proteins; D020668:rap GTP-Binding Proteins; D020742:rhoA GTP-Binding Protein