Rho GTPases of the RhoBTB subfamily and tumorigenesis

Abstract

RhoBTB proteins constitute a subfamily of atypical members within the Rho fa mily of small guanosine triphosphatases (GTPases). Their most salient feature is their domain architecture: a GTPase domain (in most cases, nonfunctional) is followed by a prolinerich region, a tandem of 2 broadcomplex, tramtrack, bric à brac (BTB) domains, and a conserved Cterminal region. In humans, the RhoBTB subfamily consists of 3 isoforms: RhoBTB1, RhoBTB2, and RhoBTB3. Orthologs are present in several other eukaryotes, such as Drosophila and Dictyostelium, but have been lost in plants and fungi. Interest in RhoBTB arose when RHOBTB2 was identified as the gene homozygously deleted in breast cancer samples and was proposed as a candidate tumor suppressor gene, a property that has been extended to RHOBTB1. The functions of RhoBTB pro teins have not been defined yet, but may be related to the roles of BTB domains in the recruitment of cullin3, a component of a family of ubiquitin ligases. A model emerges in which RhoBTB proteins are required to maintain constant levels of putative substrates involved in cell cycle regulation or vesicle transport through targeting for degradation in the 26S proteasome. RhoBTB proteins are engrossing the list of Rho GTPases involved in tumorigenesis. Unlike typical Rho GTPases (usually overexpressed or hyperactive), RhoBTB proteins appear to play a part in the carcinogenic process through a mechanism that involves the decreased or abolished expression of the corresponding genes, or more rarely, mutations that result in impaired functioning of the protein, presumably leading to the accumulation of RhoBTB substrates and alterations of the cellular homeo stasis.

Microarray Analysis Reveals Distinct Gene Expression Profiles Among Different Tumor Histology, Stage and Disease Outcomes in Endometrial Adenocarcinoma

“…Recent studies have suggested that RhoB is involved in tumor suppression. These studies suggested that RhoB was detected in normal tissue yet its expression was dramatically lost during cancer progression in lung and head and neck squamous cell carcinoma [37], [38]. In line with these findings, high expression of RhoB was associated with favorable outcome in bladder cancer.…”

Rho GTPases: Regulation and roles in cancer cell biology

“…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.…”

RHOBTB1 (Rho-related BTB domain containing 1)

“…The decrease affected to 80% of kidney and to 58% of breast cancer samples. The expression changes correlated with those of CUL3 in the same samples (Berthold et al, 2008) …”

“…RhoBTB1 binds to cullin3 and by analogy to RhoBTB2 and RhoBTB3 may constitute ubiquitin ligase complexes. RhoBTB proteins appear to exist in an inactive state through an intramolecular interaction of the BTB domain region with the GTPase domain (Berthold et al, 2008). This model has been refined recently for RhoBTB2 to show that the HSP90AA1 (Hsp90) chaperone machinery unlocks RhoBTB, enabling GTP binding and interaction with Cullin 3 and the COPS8 (COP9) signalosome.…”

“…The gene is also expressed in foetal tissues (Ramos et al, 2002;Nagase et al, 1998). Expression of RHOBTB1 has been found decreased in kidney, breast and stomach tumors in a cancer profiling array (Berthold et al, 2008), in 37% of 46 head and neck squamous cell carcinomas (Beder et al, 2006) and in colon cancer tissues (Xu et al, 2013). RHOBTB1 is a target of the microRNA MIR31- (Alder et al, 2012;Xu et al, 2013).…”