Disease relevance of RAN

• Another AR N-terminal interacting protein, ARA24, interacted with the poly-Q tract, a region within the N-terminus of the AR linked to Kennedy's disease (X-linked spinal and bulbar muscular atrophy) [1].

Psychiatry related information on RAN

• In contrast to TC1, TC4 produced a stimulant effect in locomotor activity with the ED(50) estimated at 0.94 mg/kg [2].

High impact information on RAN

• (in this issue of Cell) shows that the small GTPase Ran can directly inhibit licensing inside nuclei once CDKs are active late in the cell cycle [3].
• It discusses recently proposed models for the translocation of receptor-cargo complexes through the NPC channel and reviews how the small GTPase Ran functions as a positional marker of the genome to regulate multiple important aspects of the eukaryotic cell cycle [4].
• The small GTPase Ran, bound to GTP, is required for the induction of spindle formation by chromosomes in M phase [5].
• Type-II cyclophilin is identical to RanBP2, a large protein that binds the GTPase Ran [6].
• Characterization of proteins that interact with the cell-cycle regulatory protein Ran/TC4 [7].

Chemical compound and disease context of RAN

• Trishomocubane analogues TC1 (N-(3'-fluorophenyl)ethyl-4-azahexacyclo [5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol) and TC4 (N-(3'-fluorophenyl)methyl-4-azahexacyclo [5.4.1.0(2,6).0(3,10).0(5,9).0(8,11)]dodecan-3-ol) were evaluated for their modulatory effects on locomotor activity as well as interactions with cocaine-induced responses [2].

Biological context of RAN

• A small GTPase Ran is a key regulator for active nuclear transport [8].
• The human Ras-related nuclear protein Ran/TC4 (refs 1-4) is the prototype of a well conserved family of GTPases that can regulate both cell-cycle progression and messenger RNA transport [7].
• Transient expression of a Ran/TC4 protein with mutations expected to perturb GTP hydrolysis disrupts host cell DNA synthesis [9].
• Ran/TC4, first identified as a well-conserved gene distantly related to H-RAS, encodes a protein which has recently been shown in yeast and mammalian systems to interact with RCC1, a protein whose function is required for the normal coupling of the completion of DNA synthesis and the initiation of mitosis [9].
• High levels of the GTPase Ran/TC4 relieve the requirement for nuclear protein transport factor 2 [10].

Anatomical context of RAN

• We recently developed an assay in which nuclear export of the shuttling transcription factor NFAT (nuclear factor of activated T cells) can be reconstituted in permeabilized cells with the GTPase Ran and the nuclear export receptor CRM1 [11].
• The small GTPase Ran plays a central role in several key nuclear functions, including nucleocytoplasmic transport, cell cycle progression, and assembly of the nuclear envelope [12].
• Ran/TC4, in turn, interacts with a number of proteins that are involved in the regulation of GTP hydrolysis or are components of the nuclear pore [13].
• The molecular mechanism of nuclear envelope (NE) assembly is poorly understood, but in a cell-free system made from Xenopus eggs NE assembly is controlled by the small GTPase Ran [1,2] [14].
• 4.1R80 was efficiently imported in the nuclei of digitonin-permeabilized COS-7 cells in the presence of recombinant Rch1 (human importin alpha2), importin beta, and GTPase Ran [15].

Associations of RAN with chemical compounds

• CRM1/Exportin1 mediates the nuclear export of proteins bearing a leucine-rich nuclear export signal (NES) by forming a cooperative ternary complex with the NES-bearing substrate and the small GTPase Ran [16].
• By preloading recombinant Ran/TC4 with [gamma-32P]GTP or [3H]GDP, we show that the interactions with p97 and NTF2 are specific for the GTP- and GDP-bound forms, respectively [17].
• The linkage of Kennedy's neuron disease to ARA24, the first identified androgen receptor polyglutamine region-associated coactivator [18].
• Ran/TC4 and its guanine nucleotide release protein RCC1 have previously been implicated in DNA replication, cell cycle checkpoint control, and RNA synthesis, processing and export [19].
• Biochemical complementation with bacterially expressed protein demonstrated that this essential GTP gamma S-sensitive transport factor was Ran/TC4, a previously described GTPase of the Ras superfamily found in both nucleus and cytoplasm [19].

Physical interactions of RAN

• The C terminus of the nuclear RAN/TC4 GTPase stabilizes the GDP-bound state and mediates interactions with RCC1, RAN-GAP, and HTF9A/RANBP1 [20].
• Our data indicate that ARA24 could also interact with AR, and that this binding is decreased by an expanding poly-glutamine (Q) length within AR [21].
• The fission yeast Nup107-120 complex functionally interacts with the small GTPase Ran/Spi1 and is required for mRNA export, nuclear pore distribution, and proper cell division [22].
• The termination of export processes from the nucleus to the cytoplasm in higher eukaryotes is mediated by binding of the small GTPase Ran as part of the export complexes to the Ran-binding domains (RanBD) of Ran-binding protein 2 (RanBP2) of the nuclear pore complex [23].

Regulatory relationships of RAN

• Deletion of the acidic hexapeptide (DEDDDL) at the C terminus of ARA24 further enhances its AR coactivation [18].
• Monoclonal antibodies to NTF2 inhibit nuclear protein import by preventing nuclear translocation of the GTPase Ran [24].

Other interactions of RAN

• The Mad homology 2 (MH2) domain is responsible for Smad3 export, which requires the GTPase Ran [25].
• Receptor-mediated nucleocytoplasmic transport is dependent on the GTPase Ran and Ran-binding protein 1 (RanBP1) [26].
• A 60 kD protein, importin, is essential for the first nuclear import step, and the small G protein Ran/TC4 is essential for the second [27].
• SM is also shown to be associated in vivo with other components of the CRM 1 export pathway, including the small GTPase Ran and the nucleoporin CAN/Nup214 [28].
• At low concentrations of beta2, there was no stimulation of import by the exogenous addition of the GTPase Ran [29].

Analytical, diagnostic and therapeutic context of RAN

• Using the two-hybrid method, we isolated a Saccharomyces cerevisiae cDNA encoding a protein homologous to Schizosaccharomyces pombe protein Dis3sp, using as bait, human GTPase Ran [30].
• Differential-display reverse transcriptase PCR product assayed by capillary electrophoresis revealed the small GTPase Ran, regulating nuclear import and export of proteins [31].

References