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.

Keywords: HIFα; Rab9; RhoBTB; cullin; cyclin E; tumor suppressor; ubiquitination.

Figure 1

Architecture of RhoBTB proteins and proposed mechanism of regulation. (a) Domain structure of RhoBTB proteins. The GTPase domain is followed by a proline-rich region, a tandem of two BTB (broad complex, tramtrack, and bric-a-brac) domains (the first one is bipartite) and a carboxyl terminal BACK (BTB and C-terminal Kelch) domain. The cartoon is drawn roughly to scale and fits RhoBTB1 and RhoBTB2. RhoBTB3 has a shorter insert in the first BTB domain and it bears an isoprenylation (CAAX) motif at the end; and (b) a model depicting the hypothetical mechanism of activation and inactivation of RhoBTB. An intramolecular interaction of the GTPase domain with the first BTB domain maintains the molecule inactive. Interaction with specific ligands would provoke a conformational change that disrupts the intramolecular interaction. There is probably not a unique ligand binding site that causes activation of RhoBTB (two have been depicted in this model as examples). The GTPase domain would then be able to bind and hydrolyze GTP (in the case of RhoBTB2 and probably also RhoBTB1) or ATP (in the case of RhoBTB3) and the first BTB domain would be free to assemble a cullin 3-dependent ubiquitin ligase complex that would tag the ligands, as well as RhoBTB itself, for degradation in the proteasome. It has not been established whether nucleotide binding and cullin 3 binding are always linked.

Figure 2

Schematic illustrating the roles of RhoBTB proteins in tumorigenesis and other processes. Proposed mechanisms for (a) RhoBTB2 and (b) RhoBTB3 are shown. RhoBTB1 (not depicted) is likely to function similarly to RhoBTB2 but has not been investigated extensively. Blue arrows indicate factors that affect the expression of the RhoBTB-encoding gene. Green arrows indicate positive or stimulatory links. Red arrows indicate inhibitory links. Interacting cullins are indicated with black arrows. The arrows do not implicate direct interactions; see Table 1 for details on interactions. Recognized substrates of RhoBTB3-dependent ubiquitin ligase complexes are shown in blue. Multiprotein complexes are boxed.