Signaling by Rho GTPases, Miro GTPases and RHOBTB3

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Homo sapiens
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RAS-like proteins are small GTP binding proteins characterized structurally by 5 G boxes that are involved in nucleotide binding and hydrolysis. RAS-like proteins are typically active when bound to GTP and inactive when bound to GDP. Conversion between the two states is mediated by effector proteins: among others, GTPase activating proteins (GAPs) enable hydrolysis of bound GTP to form GDP, which remains bound, and guanine nucleotide exchange factors (GEFs) enable exchange of bound GDP for free GTP (intracellular GTP concentrations are typically an order of magnitude higher than GDP concentrations) (reviewed in Tetlow and Tamanoi, 2013).

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 (Boureux et al. 2007). MIRO proteins have intrinsically high GTPase activity and do not require GTPase activator proteins (Peters et al. 2018). 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 (Espinosa et al. 2009). RHOBTB3 is involved in CUL3 dependent protein ubiquitination (Berthold et al. 2008; Ji and Rivero 2016), retrograde transport from endosomes to the Golgi apparatus (Espinosa et al. 2009), regulation of the cell cycle and in modulating the adaptive response to hypoxia (Ji and Rivero 2016).

Literature References
PubMed ID Title Journal Year
27314390 Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis

Ji, W, Rivero, F

Cells 2016
25033798 The Ras superfamily G-proteins

Tetlow, AL, Tamanoi, F

Enzymes 2013
18298893 Rho GTPases of the RhoBTB subfamily and tumorigenesis

Berthold, J, Schenkova, K, Rivero, F

Acta Pharmacol. Sin. 2008
24256248 Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins

Birsa, N, Norkett, R, Higgs, N, Lopez-Domenech, G, Kittler, JT

Biochem. Soc. Trans. 2013
27548350 Rho GTPases, their post-translational modifications, disease-associated mutations and pharmacological inhibitors

Olson, MF

Small GTPases 2018
27301673 Regulating Rho GTPases and their regulators

Hodge, RG, Ridley, AJ

Nat. Rev. Mol. Cell Biol. 2016
30513825 Human Miro Proteins Act as NTP Hydrolases through a Novel, Non-Canonical Catalytic Mechanism

Peters, DT, Kay, L, Eswaran, J, Lakey, JH, Soundararajan, M

Int J Mol Sci 2018
17035353 Evolution of the Rho family of ras-like GTPases in eukaryotes

Boureux, A, Vignal, E, Faure, S, Fort, P

Mol Biol Evol 2007
19490898 RhoBTB3: a Rho GTPase-family ATPase required for endosome to Golgi transport

Espinosa, EJ, Calero, M, Sridevi, K, Pfeffer, SR

Cell 2009
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