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.
Highlights
Ras superfamily small guanosine triphosphatases (GTPases) are important molecular switches that regulate a myriad of signaling pathways in eukaryotes
The GTPase cycle of Rho proteins is characteristically modulated by three major classes of proteins that are targets of upstream signaling pathways: guanine nucleotide exchange factors (GEFs) catalyze the exchange of GDP for GTP to activate the switch; GTPase activating proteins (GAPs) stimulate the intrinsic GTPase activity and, inactivate the switch; guanine nucleotide-dissociation inhibitors (GDIs) play complex roles stabilizing the GTPase and regulating exchange between membranes and cytosol
The effect on cyclin D1 is only partially dependent on proteasomal degradation [43]. It has not been investigated whether cyclin D1 or any other cyclin is targeted by RhoBTB2 for ubiquitination
Summary
Ras superfamily small guanosine triphosphatases (GTPases) are important molecular switches that regulate a myriad of signaling pathways in eukaryotes They characteristically cycle between an active GTP-bound state and an inactive GDP-bound state. Ras superfamily Rho GTPases are key regulators of the actin filament system and, of all processes that depend on the reorganization of the actin cytoskeleton, such as membrane trafficking, cell motility, cytokinesis, adhesion, and morphogenesis They have been found implicated in numerous processes not directly linked to actin reorganization, like NADPH oxidase activation, microtubule organization, gene expression, cell cycle progression, apoptosis, and tumorigenesis [2,3]. RhoBTB proteins have a peculiar domain architecture with a long extension following the GTPase domain Their cellular roles bear no apparent relationship to direct remodeling of the cytoskeleton. In this review we shall present and discuss our current knowledge about the emerging functions of human RhoBTB proteins and their associated molecular mechanisms, with the occasional reference to studies carried out in mouse models
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