Conserved Rho-regulated signaling pathways: from cytoskeleton remodeling to ubiquitination by RhoBTB proteins

Abstract

Rho GTPases have been implicated mainly in regulation of the cytoskeleton, but they also participate in processes as diverse as vesicle trafficking, cell cycle regulation, apoptosis and tumorigenesis. We recently identified an atypical subfamily of Rho GTPases, RhoBTB, which is represented in vertebrates, Drosophila and Dictyostelium. The role of RhoBTB proteins is largely unknown. Recent studies demonstrate that BTB domain-containing proteins are involved in the formation of cullin 3-dependent ubiquitin ligase complexes. We are addressing the function of RhoBTB in two model systems, mammalian and Dictyostelium cells. Using two-hybrid and coimmunoprecipitation we are examining binding of mammalian RhoBTB3 to cullins. We also found that RhoBTB3 is degraded in the proteasomal apparatus, and a two-hybrid screening yielded three potential targets. In addition, a role for RhoBTB2 as a tumor suppressor has been proposed, and in fact we show that expression profiles of RhoBTB genes and cullin3 differ between normal and tumoral human tissues. In parallel we are analyzing a Dictyostelium strain that lacks RacA, the RhoBTB homolog, and searching for effectors of the GTPase domain. We propose a model in which RhoBTB proteins function as specific adaptors for the degradation of proteins involved in cytoskeleton remodeling and in control of cell proliferation.