guanosine-diphosphate and Neoplasm-Metastasis

Rac GTPases are crucial signaling regulators in eukaryotic cells, acting downstream of many cell surface receptors. They play essential roles in diverse cellular functions including cytoskeleton dynamics, cell motility, cell survival and apoptosis. Their activities are controlled by a tightly regulated GDP/GTP cycle coupled with an alternation between cytoplasm and membrane compartments. Aberrant Rac signaling is found in some human cancers as a result of changes in the GTPase itself or in its regulation loops. This review highlights recent findings regarding the molecular and functional aspects of Rac that mediate tumorigenic transformation and metastasis. It also describes the cellular mechanisms that potentially explain the complex role of Rac in tumorigenesis. Finally, it discusses approaches for modulating Rac function as a potential anticancer strategy.

Topics: Animals; Antineoplastic Agents; Guanosine Diphosphate; Guanosine Triphosphate; Humans; Mice; Mice, Knockout; NADPH Oxidases; Neoplasm Invasiveness; Neoplasm Metastasis; Neoplasms; Neovascularization, Pathologic; rac GTP-Binding Proteins

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.

Topics: 3T3 Cells; Animals; Cell Line; Cell Membrane; Cell Transformation, Neoplastic; Fibroblasts; Glutathione Transferase; GTP Phosphohydrolases; GTP-Binding Proteins; Guanine Nucleotide Exchange Factors; Guanosine 5'-O-(3-Thiotriphosphate); Guanosine Diphosphate; Mice; Neoplasm Invasiveness; Neoplasm Metastasis; Proteins; rac GTP-Binding Proteins; rap GTP-Binding Proteins; Recombinant Fusion Proteins; rhoA GTP-Binding Protein; T-Lymphoma Invasion and Metastasis-inducing Protein 1; Transfection; Tumor Cells, Cultured