Role of Rho-like proteins of the RhoBTB family in oncogenesis

Abstract

Abstract of the 8th Joint Meeting of the Signal Transduction Society STS, Hilton Hotel, Weimar, 4–6 November 2004: Workshop E: “Interaction Domains and Signaling Complexes.Rho proteins have been implicated mainly in the regulation of the cytoskeleton, but also in vesicle trafficking,phagocytosis and transcriptional activation. They participate in tumorigenesis, where some of them are overfunc-tional. A subfamily of Rho GTPases, RhoBTB proteins, is represented by three isoforms in vertebrates: RhoBTB1,RhoBTB2 and RhoBTB3. They are around 600 amino acids long and consist of a GTPase domain, a prolin richregion, two BTB domains and a carboxyl-terminal region. The role of RhoBTB proteins is at present unknown.Tissue distribution studies by means of in situ hybridization detected the expression of RhoBTB1 and RhoBTB3specifically in vascular endothelial cells suggesting a role in angiogenesis. In addition, a role for RhoBTB2 as atumor suppressor has been proposed, and in fact we show that expression profiles of RhoBTB genes differbetween normal and tumoral human tissuesRhoBTB3 is targeted to Golgi membranes through a prenylation motif. RhoBTB1 and RhoBTB2 lack this motif,but localize at aggregates distinct from vesiclular structures like Golgi apparatus or lysosomes. We generatedtruncated contructs in order to identify the sequence responsible for targeting of RhoBTB1 and RhoBTB2 tothese aggregates.Recent studies demonstrate that BTB domain-containing proteins are involved in the formation of Cullin 3 depen-dent ubiquitin ligase complexes. Cullins are subunits of a prominent class of RING ubiquitin ligases. Using yeasttwo hybrid and coimmunoprecipitation studies we show that RhoBTB3 binds to Cullin 3 and might also be de-graded in the proteasomal apparatus. We propose a model in which RhoBTB proteins function as specific adap-tors for the degradation of unknown proteins involved in the control of cell proliferation and have identified poten-tial targets using a two-hybrid approach.Peer Reviewe