Signaling by Rho GTPases, Miro GTPases and RHOBTB3

The human genome includes over 150 members of the RAS superfamily grouped into five main subfamilies: RAS, RHO, ARF, RAB and RAN. These small GTPases affect a wide range of critical processes including gene expression, signal transduction, cell morphology, vesicle and nuclear trafficking, cellular proliferation and motility, among others (reviewed in Tetlow and Tamanoi, 2013).

The RHO family of GTPases is large and diverse, with many of its members considered to be master regulators of actin cytoskeleton, involved in the regulation of cellular processes that depend on dynamic reorganization of the cytoskeleton, including cell migration, cell adhesion, cell division, establishment of cellular polarity and intracellular transport (reviewed in Hodge and Ridley 2016, and Olson 2018).

MIRO proteins and RHOBTB3 protein, sometimes called atypical RHO proteins, show a high degree of overall sequence similarity to members of the five RAS-like subfamilies but diverge in their functions enough to constitute two separate subfamilies. MIRO proteins have intrinsically high GTPase activity and do not require GTPase activator proteins. They play an important role mitochondrial biogenesis, maintenance and organization (reviewed in Birsa et al. 2013). The GTPase domain of RHOBTB3 is divergent from other Ras like superfamily members and displays ATPase activity. RHOBTB3 is involved in CUL3 dependent protein ubiquitination, retrograde transport from endosomes to the Golgi apparatus, regulation of the cell cycle and in modulating the adaptive response to hypoxia.