Reactome | Signaling by Rho GTPases, Miro GTPases and RHOBTB3

Signaling by Rho GTPases, Miro GTPases and RHOBTB3

Stable Identifier

R-HSA-9716542

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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Signaling by Rho GTPases, Miro GTPases and RHOBTB3

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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
25033798	The Ras superfamily G-proteins Tamanoi, F, Tetlow, AL	Enzymes	2013
27314390	Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis Ji, W, Rivero, F	Cells	2016
18298893	Rho GTPases of the RhoBTB subfamily and tumorigenesis Schenkova, K, Berthold, J, Rivero, F	Acta Pharmacol. Sin.	2008
24256248	Mitochondrial trafficking in neurons and the role of the Miro family of GTPase proteins Norkett, R, Higgs, N, Lopez-Domenech, G, Birsa, N, 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 Ridley, AJ, Hodge, RG	Nat. Rev. Mol. Cell Biol.	2016
30513825	Human Miro Proteins Act as NTP Hydrolases through a Novel, Non-Canonical Catalytic Mechanism Lakey, JH, Kay, L, Soundararajan, M, Eswaran, J, Peters, DT	Int J Mol Sci	2018
17035353	Evolution of the Rho family of ras-like GTPases in eukaryotes Fort, P, Faure, S, Vignal, E, Boureux, A	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