Atypical Rho GTPases of the RhoBTB Subfamily: Roles in Vesicle Trafficking and Tumorigenesis

Abstract

RhoBTB proteins constitute a subfamily of atypical Rho GTPases represented in mammals by RhoBTB1, RhoBTB2, and RhoBTB3. Their characteristic feature is a carboxyl terminal extension that harbors two BTB domains capable of assembling cullin 3-dependent ubiquitin ligase complexes. The expression of all three RHOBTB genes has been found reduced or abolished in a variety of tumors. They are considered tumor suppressor genes and recent studies have strengthened their implication in tumorigenesis through regulation of the cell cycle and apoptosis. RhoBTB3 is also involved in retrograde transport from endosomes to the Golgi apparatus. One aspect that makes RhoBTB proteins atypical among the Rho GTPases is their proposed mechanism of activation. No specific guanine nucleotide exchange factors or GTPase activating proteins are known. Instead, RhoBTB might be activated through interaction with other proteins that relieve their auto-inhibited conformation and inactivated through auto-ubiquitination and destruction in the proteasome. In this review we discuss our current knowledge on the molecular mechanisms of action of RhoBTB proteins and the implications for tumorigenesis and other pathologic conditions.

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“…S5). RHOBTB2 is a tumor suppressor that is upregulated during drug-induced apoptosis and inhibits AKT (29,30). Thus, its inactivation may contribute to drug resistance.…”

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“…44,118 The Rho domain of RhoBTB1 and RhoBTB2 contains the amino acid motifs required for GTP-binding but is around 18 residues longer and rich in charged residues. 120,121 The GTP-binding domain of RhoBTBs is expected not to hydrolyse GTP, because they do not have key amino acids required for GTP hydrolysis, including a glycine equivalent to G12 and a glutamine equivalent to Q61 in Ras. 121,122 It has been reported that the GTP-binding domain of RhoBTB2 binds to GTP in vitro, 120 but nothing has been published for RhoBTB1.…”

“…120,121 The GTP-binding domain of RhoBTBs is expected not to hydrolyse GTP, because they do not have key amino acids required for GTP hydrolysis, including a glycine equivalent to G12 and a glutamine equivalent to Q61 in Ras. 121,122 It has been reported that the GTP-binding domain of RhoBTB2 binds to GTP in vitro, 120 but nothing has been published for RhoBTB1. RhoBTB1 and RhoBTB2 are also bigger than classical GTPases due to the presence of extra domains including 2 broad-complex, tramtrack, bric a brac (BTB) domains, which are conserved proteinprotein interaction domains.…”

Open questions: what about the ‘other’ Rho GTPases?

“…RhoU and RhoV have high intrinsic GDP/GTP exchange rates, so are unlikely to need GEFs for activation but could still be turned off by GAPs [ 1 , 4 ]. For two other members, RhoBTB1 and RhoBTB2, the Rho domains are quite divergent in sequence from other family members and they are unlikely to be regulated by GEFs or GAPs [ 5 ].…”

“…The exception is the Rnd proteins, for which several new targets have been identified by yeast two-hybrid screening, although so far we know relatively little about the functional consequences of these interactions [ 7 ]. RhoBTB proteins have been shown to interact via their BTB domains with Cullin-3, a scaffold for ubiquitin ligase complexes, but again the functional role of this interaction is not clear [ 5 ]. A challenge for the future will be to identify the protein interactome for each Rho GTPase and to determine how their interactions change dynamically during cellular responses and vary between cell types and with external conditions.…”