RAN

Summary

RAN (RAN, member RAS oncogene family, HGNC:9846) is a protein-coding gene on chromosome 12q24.33, encoding GTP-binding nuclear protein Ran (P62826). GTPase involved in nucleocytoplasmic transport, participating both to the import and the export from the nucleus of proteins and RNAs. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

RAN (ras-related nuclear protein) is a small GTP binding protein belonging to the RAS superfamily that is essential for the translocation of RNA and proteins through the nuclear pore complex. The RAN protein is also involved in control of DNA synthesis and cell cycle progression. Nuclear localization of RAN requires the presence of regulator of chromosome condensation 1 (RCC1). Mutations in RAN disrupt DNA synthesis. Because of its many functions, it is likely that RAN interacts with several other proteins. RAN regulates formation and organization of the microtubule network independently of its role in the nucleus-cytosol exchange of macromolecules. RAN could be a key signaling molecule regulating microtubule polymerization during mitosis. RCC1 generates a high local concentration of RAN-GTP around chromatin which, in turn, induces the local nucleation of microtubules. RAN is an androgen receptor (AR) coactivator that binds differentially with different lengths of polyglutamine within the androgen receptor. Polyglutamine repeat expansion in the AR is linked to Kennedy’s disease (X-linked spinal and bulbar muscular atrophy). RAN coactivation of the AR diminishes with polyglutamine expansion within the AR, and this weak coactivation may lead to partial androgen insensitivity during the development of Kennedy’s disease.

Source: NCBI Gene 5901 — RefSeq curated summary.

At a glance

• Clinical variants (ClinVar): 10 total
• Druggable target: yes — 1 molecules with ChEMBL bioactivity
• Cancer dependency (DepMap): dependent in 100.0% of screened cell lines (common-essential)
• MANE Select transcript: NM_006325

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:9846
Approved symbol	RAN
Name	RAN, member RAS oncogene family
Location	12q24.33
Locus type	gene with protein product
Status	Approved
Aliases	ARA24, TC4, Gsp1
Ensembl gene	ENSG00000132341
Ensembl biotype	protein_coding
OMIM	601179
Entrez	5901

Gene structure

Transcript identifiers

Ensembl transcripts: 15 — 10 protein_coding, 4 retained_intron, 1 nonsense_mediated_decay

ENST00000392367, ENST00000392369, ENST00000448750, ENST00000464211, ENST00000477395, ENST00000535090, ENST00000536606, ENST00000537745, ENST00000539498, ENST00000541630, ENST00000541679, ENST00000543796, ENST00000857526, ENST00000857527, ENST00000857528

RefSeq mRNA: 3 — MANE Select: NM_006325 NM_001300796, NM_001300797, NM_006325

CCDS: CCDS73546, CCDS9271

Canonical transcript exons

ENST00000543796 — 7 exons

Exon	Start	End
ENSE00001953083	130875882	130877678
ENSE00002228967	130872066	130872126
ENSE00003487832	130873003	130873128
ENSE00003525542	130874546	130874733
ENSE00003562063	130872836	130872920
ENSE00003566649	130875612	130875782
ENSE00003736927	130872584	130872629

Expression profiles

Bgee: expression breadth ubiquitous, 287 present calls, max score 99.76.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 313.5025 / max 3966.6034, expressed in 1828 samples.

FANTOM5 promoters (1 alternative TSS)

Promoter ID	TPM avg	Samples expressed
128739	313.5025	1828

Top tissues by expression

288 total, by Bgee expression score (0-100, higher = more expressed):

Tissue	Anatomy ID	Expression score	Quality
primordial germ cell in gonad	CL:0000670 ∩ UBERON:0000991	99.76	gold quality
ventricular zone	UBERON:0003053	99.68	gold quality
ganglionic eminence	UBERON:0004023	99.61	gold quality
left testis	UBERON:0004533	99.59	gold quality
right testis	UBERON:0004534	99.59	gold quality
stromal cell of endometrium	CL:0002255	99.47	gold quality
cortical plate	UBERON:0005343	99.36	gold quality
right adrenal gland	UBERON:0001233	99.24	gold quality
mucosa of transverse colon	UBERON:0004991	99.24	gold quality
adrenal tissue	UBERON:0018303	99.20	gold quality
left adrenal gland	UBERON:0001234	99.18	gold quality
testis	UBERON:0000473	99.15	gold quality
left adrenal gland cortex	UBERON:0035825	99.14	gold quality
right adrenal gland cortex	UBERON:0035827	99.14	gold quality
rectum	UBERON:0001052	99.13	gold quality
esophagus mucosa	UBERON:0002469	99.12	gold quality
adenohypophysis	UBERON:0002196	99.03	gold quality
upper lobe of left lung	UBERON:0008952	99.00	gold quality
body of stomach	UBERON:0001161	98.99	gold quality
esophagus	UBERON:0001043	98.97	gold quality
left coronary artery	UBERON:0001626	98.94	gold quality
colonic epithelium	UBERON:0000397	98.93	gold quality
metanephros cortex	UBERON:0010533	98.91	gold quality
prefrontal cortex	UBERON:0000451	98.90	gold quality
transverse colon	UBERON:0001157	98.90	gold quality
lower esophagus mucosa	UBERON:0035834	98.90	gold quality
omental fat pad	UBERON:0010414	98.89	gold quality
peritoneum	UBERON:0002358	98.88	gold quality
small intestine Peyer’s patch	UBERON:0003454	98.87	gold quality
lower esophagus	UBERON:0013473	98.87	gold quality

Single-cell (SCXA)

Detected in 27 experiment(s), a significant marker in 18.

Experiment	Marker?	Max mean expression
E-CURD-7	yes	2380.52
E-ENAD-21	yes	1905.57
E-MTAB-9067	yes	910.00
E-HCAD-4	yes	156.63
E-CURD-112	yes	42.69
E-HCAD-10	yes	41.66
E-GEOD-134144	yes	29.54
E-CURD-46	yes	28.67
E-GEOD-125970	yes	27.45
E-CURD-122	yes	26.30
E-HCAD-13	yes	25.25
E-HCAD-1	yes	19.81
E-HCAD-9	yes	16.79
E-MTAB-10042	yes	13.35
E-MTAB-10553	yes	9.03

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): MYC

miRNA regulators (miRDB)

90 targeting RAN, top 30 by miRDB confidence (max_score; target_count = how many genes the miRNA targets in total — lower means more specific):

miRNA	Max score	Avg score	miRNA target_count
HSA-MIR-4776-3P	100.00	68.73	1340
HSA-MIR-3613-3P	100.00	76.36	7965
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-513A-5P	100.00	69.77	2465
HSA-MIR-181A-5P	99.99	72.96	2995
HSA-MIR-181B-5P	99.99	72.97	2996
HSA-MIR-181C-5P	99.99	72.95	2996
HSA-MIR-181D-5P	99.99	73.04	2997
HSA-MIR-1184	99.99	68.19	1458
HSA-MIR-19A-3P	99.98	75.33	2762
HSA-MIR-19B-3P	99.98	75.44	2754
HSA-MIR-103A-3P	99.98	69.14	1595
HSA-MIR-107	99.98	69.14	1595
HSA-MIR-607	99.97	73.62	5593
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-5688	99.96	73.23	4504
HSA-MIR-495-3P	99.96	72.81	4197
HSA-MIR-1250-3P	99.96	70.04	4038
HSA-MIR-1468-3P	99.96	72.74	3797
HSA-LET-7C-3P	99.95	73.42	2862
HSA-MIR-4760-3P	99.93	70.50	2385
HSA-MIR-450B-5P	99.92	71.48	3175
HSA-MIR-454-3P	99.91	74.01	1925
HSA-MIR-10523-5P	99.91	69.22	2038
HSA-MIR-3671	99.90	73.04	3897
HSA-MIR-130A-3P	99.90	73.31	1861
HSA-MIR-130B-3P	99.90	73.27	1850
HSA-MIR-301A-3P	99.90	73.15	1839
HSA-MIR-301B-3P	99.90	73.19	1836
HSA-MIR-3666	99.90	73.24	1833

Functional genomics

DepMap (CRISPR cell-line fitness): dependent in 100.0% of screened cell lines, common-essential.

Literature-anchored findings (GeneRIF, showing 40)

• GTP-binding proteins G(salpha), G(ialpha), and Ran identified in mitochondria of human placenta (PMID:11779226)
• C terminus of Ran is a major determinant of the state of Ran, and that removal of this allows the GDP-bound form to adopt a GTP-like conformation, thereby creating a constitutively active protein. (PMID:12051861)
• chromosomal interactions during meiosis and mitosis (PMID:12415012)
• structure of the Ran-RanBP1-RanGAP complex (PMID:14585972)
• Ran modulates at least two processes involved in spindle assembly (PMID:14600264)
• data suggest that HPV16 E7 translocates through the nuclear pores via a nonclassical Ran-dependent pathway, independent of the main cytosolic Kap beta import receptors (PMID:14675621)
• the cell-cycle machinery directly regulates the Ran-signaling pathway by placing a high RanGTP concentration on the mitotic chromosome; RCC1 to couples RanGTP production to chromosome binding (PMID:15014043)
• nuclear import of the transcription factor PU.1 occurs via RanGTP-stimulated binding to Nup153 (PMID:15632149)
• Keratin sequestration of oxidized Ran may provide a back-up protective mechanism in some cases of oxidative injury (PMID:15691838)
• Review proposes that Ran/Crm1 may act as a ’loading dock’ to coordinate various checkpoint factors in regulating the fidelity of centrosome duplication during cell cycle progression. (PMID:16294017)
• Findings indicate that the decrease in ATP levels induced by cellular stress causes a decrease in RanGTP levels and a collapse of Ran distribution in the cytoplasmic and nuclear compartments. (PMID:16368437)
• Phosphorylated wild type RanGAP1, but not a mutant harboring a mutation at the phosphorylation site 358S, efficiently formed a stable ternary complex with Ran and RanBP1 in vivo, suggesting that the 358S phosphorylation of RanGAP1 affects the Ran system. (PMID:16428860)
• Exportin 4 is sufficient for carrying the in vitro nuclear export of Smad3 in cooperation with Ran. (PMID:16449645)
• results demonstrate that conserved Ran-regulated pathways are involved in multiple, parallel processes required for spindle function, but that their relative contribution differs in chromatin- versus centrosome/kinetochore-driven spindle assembly systems (PMID:16572176)
• High level of Ran appears to be more tightly associated with a poor prognosis. (PMID:16572426)
• Multiple nuclear exclusion motifs and a nuclear localization domain control PTEN nuclear localization by a Ran-dependent mechanism and suggest a proapoptotic role for PTEN in the cell nucleus. (PMID:16807353)
• Plk1 regulates the spindle organization partially through its phosphorylation on Ran (PMID:16930555)
• studies elucidate the Ran-binding interface on Nup153 and, more broadly, provide insight into the versatility of this zinc finger binding module (PMID:17426026)
• developed a spatial model that allowed the simulation of RanGTP production with different degrees of chromosome alignment in mitosis (PMID:17671426)
• Ran system is a target of hyperosmotic stress signaling, and cells use protein localization-based mechanisms as part of a rapid stress response (PMID:17761537)
• A cell-free import assay showed that the nuclear transport of the human herpesvirus 6 U69 protein was mediated by importin alpha/beta in conjunction with the small GTPase Ran. (PMID:18003734)
• High expression of Ran GTPase is associated with local invasion and metastasis of human clear cell renal cell carcinoma (PMID:18241036)
• Results report that NTF2 and Ran control nuclear import of the filamentous actin capping protein CapG. (PMID:18266911)
• Ran-GTP-mediated cargo release promotes the accumulation of hKid on chromosomes. (PMID:18268099)
• The complex of RanGTP, the export receptor Crm1, and nuclear export signal-bearing proteins regulates microtubule nucleation at kinetochores. (PMID:18287525)
• RanBP10 might serve as a molecular link between Ran and noncentrosomal microtubules (PMID:18347012)
• These data demonstrate that ARA24/Ran increases AR transactivation by enhancing the androgen receptor N-C interaction in the nucleus. (PMID:18565325)
• Survivin is a novel effector of Ran signaling, and this pathway may be preferentially exploited for spindle assembly in tumor cells. (PMID:18591255)
• Ran is a novel negative regulator of nuclear VRK1 and VRK2 kinase activity, which may vary in different subcellular localizations generating an asymmetric intracellular distribution of kinase activity depending on local protein interactions. (PMID:18617507)
• These results suggest that Ran suppresses paclitaxel-induced cell death through the downregulation of JNK-mediated signal pathways. (PMID:18690538)
• Data show the crystal structure of the Kap95p-RanGDP complex shows that Kap95p induces the switch I and II regions of RanGDP to adopt a conformation that resembles that of the GTP-bound form. (PMID:18708071)
• reduction of the affinity by RanGTP really occurs at the nucleoplasmic side of the entire nuclear pore complex (PMID:18845677)
• Therefore, we propose that RCC1 reads the histone code created by caspase-activated Mst1 to initiate apoptosis by reducing the level of RanGTP in the nucleus. (PMID:19060893)
• Data provide a molecular explanation for the assembly of the apoptotic microtubule network, and suggest important similarities with the process of RanGTP- and TPX2-mediated mitotic spindle formation. (PMID:19208764)
• study presents the crystal structure of the SPN1.CRM1.RanGTP export complex at 2.5 angstrom resolution (where SPN1 is snurportin1 and RanGTP is guanosine 5’ triphosphate-bound Ran (PMID:19389996)
• Data show that ARHI could compete for Ran-importin binding and induce disruption of importin-binding to cargo proteins, including STAT3. (PMID:19435463)
• Data show that the interaction between Ran-GDP and importin-beta promotes the dissociation of GDP from Ran. The release of GDP from the Ran-GDP-importin-beta complex stabilizes the complex, which cannot be dissociated by importin-alpha. (PMID:19549784)
• RAN GTPase is a RASSF1A effector involved in controlling microtubule organization. (PMID:19559616)
• the small GTPase RAN is a novel MAD2B binding protein (PMID:19753112)
• Ran-GTP generated at chromatin is highly mobile and interacts dynamically with distal structures that are involved in nuclear transport and mitotic spindle assembly. (PMID:19765287)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	ran	ENSDARG00000057026
mus_musculus	Ran	ENSMUSG00000029430
rattus_norvegicus	Rasl2-9	ENSRNOG00000032913
drosophila_melanogaster	Ran-like	FBGN0036497
caenorhabditis_elegans		WBGENE00004302

Protein

Protein identifiers

GTP-binding nuclear protein Ran — P62826 (reviewed: P62826)

Alternative names: Androgen receptor-associated protein 24, GTPase Ran, Ras-like protein TC4, Ras-related nuclear protein

All UniProt accessions (7): P62826, A0A087X0W0, B4DV51, B5MDF5, F5H018, H0YFC6, J3KQE5

UniProt curated annotations — full annotation on UniProt →

Function. GTPase involved in nucleocytoplasmic transport, participating both to the import and the export from the nucleus of proteins and RNAs. Switches between a cytoplasmic GDP- and a nuclear GTP-bound state by nucleotide exchange and GTP hydrolysis. Nuclear import receptors such as importin beta bind their substrates only in the absence of GTP-bound RAN and release them upon direct interaction with GTP-bound RAN, while export receptors behave in the opposite way. Thereby, RAN controls cargo loading and release by transport receptors in the proper compartment and ensures the directionality of the transport. Interaction with RANBP1 induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins. RAN (GTP-bound form) triggers microtubule assembly at mitotic chromosomes and is required for normal mitotic spindle assembly and chromosome segregation. Required for normal progress through mitosis. The complex with BIRC5/survivin plays a role in mitotic spindle formation by serving as a physical scaffold to help deliver the RAN effector molecule TPX2 to microtubules. Acts as a negative regulator of the kinase activity of VRK1 and VRK2. Enhances AR-mediated transactivation. Transactivation decreases as the poly-Gln length within AR increases.

Subunit / interactions. Monomer. Interacts with RANGAP1, which promotes RAN-mediated GTP hydrolysis. Interacts with KPNB1. Interaction with KPNB1 inhibits RANGAP1-mediated stimulation of GTPase activity. Interacts with RCC1 which promotes the exchange of RAN-bound GDP by GTP. Interaction with KPNB1 inhibits RCC1-mediated exchange of RAN-bound GDP by GTP. Interacts (GTP-bound form) with TNPO1; the interaction is direct. Interacts (GTP-bound form) with TNPO3; the interaction is direct. Interacts with KPNB1 and with TNPO1; both inhibit RAN GTPase activity. Interacts (via C-terminus) with RANBP1, which alleviates the inhibition of RAN GTPase activity. Interacts with RANGRF, which promotes the release of bound guanine nucleotide. RANGRF and RCC1 compete for an overlapping binding site on RAN. Identified in a complex with KPNA2 and CSE1L; interaction with RANBP1 mediates dissociation of RAN from this complex. Interaction with both RANBP1 and KPNA2 promotes dissociation of the complex between RAN and KPNB1. Identified in a complex composed of RAN, RANGAP1 and RANBP1. Identified in a complex that contains TNPO1, RAN and RANBP1. Identified in a nuclear export complex with XPO1. Found in a nuclear export complex with RANBP3 and XPO1. Interacts with RANBP2/NUP358. Interaction with RANBP1 or RANBP2 induces a conformation change in the complex formed by XPO1 and RAN that triggers the release of the nuclear export signal of cargo proteins. Component of a nuclear export receptor complex composed of KPNB1, RAN, SNUPN and XPO1. Found in a nuclear export complex with RAN, XPO5 and pre-miRNA. Interacts (GTP-bound form) with XPO5. Part of a complex consisting of RANBP9, RAN, DYRK1B and COPS5. Interacts with RANBP9 and RANBP10. Interacts in its GTP-bound form with BIRC5/survivin at S and M phases of the cell cycle. Interacts with TERT; the interaction requires hydrogen peroxide-mediated phosphorylation of TERT and transports TERT to the nucleus. Interacts with MAD2L2. Interacts with VRK1 and VRK3. Interacts with isoform 1 and isoform 2 of VRK2. Interacts with NEMP1 and KPNB1. Interacts (GDP-bound form) with NUTF2; regulates RAN nuclear import. Interacts with CAPG; mediates CAPG nuclear import. Interacts with NUP153. Interacts with the AR N-terminal poly-Gln region; the interaction with AR is inversely correlated with the poly-Gln length. Interacts with MYCBP2, which promotes RAN-mediated GTP hydrolysis. Interacts with EPG5. (Microbial infection) In case of HIV-1 infection, found in a complex with HIV-1 Rev, RNAs containing a Rev response element (RRE) and XPO1. (Microbial infection) Found in a complex with HTLV-1 Rex, RANBP3 and XPO1. (Microbial infection) Interacts with Mengo encephalomyocarditis virus Leader protein; the complex L-RAN recruits cellular kinases responsible for the L-induced nucleocytoplasmic trafficking inhibition.

Subcellular location. Nucleus. Nucleus envelope. Cytoplasm. Cytosol. Melanosome.

Tissue specificity. Expressed in a variety of tissues.

Post-translational modifications. Acetylation by KAT5 at Lys-134 is increased during mitosis, impairs RANGRF binding and enhances RCC1 binding. Acetylation at Lys-37 enhances the association with nuclear export components. Deacetylation of Lys-37 by SIRT7 regulates the nuclear export of NF-kappa-B subunit RELA/p65.

Cofactor. Mg(2+) interacts primarily with the phosphate groups of the bound guanine nucleotide.

Similarity. Belongs to the small GTPase superfamily. Ran family.

RefSeq proteins (3): NP_001287725, NP_001287726, NP_006316* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001806	Small_GTPase	Family
IPR002041	Ran_GTPase	Family
IPR005225	Small_GTP-bd	Domain
IPR027417	P-loop_NTPase	Homologous_superfamily

Pfam: PF00071

Catalyzed reactions (Rhea), 1 shown:

• GTP + H2O = GDP + phosphate + H(+) (RHEA:19669)

UniProt features (70 total): mutagenesis site 14, strand 12, helix 12, modified residue 9, turn 6, binding site 5, cross-link 3, region of interest 3, sequence conflict 2, initiator methionine 1, chain 1, site 1, domain 1

Structure

Experimental structures (PDB)

139 structures, top 30 by resolution.

PDB	Method	Resolution (Å)
3GJ0	X-RAY DIFFRACTION	1.48
7MO5	X-RAY DIFFRACTION	1.55
7MO1	X-RAY DIFFRACTION	1.6
5CIQ	X-RAY DIFFRACTION	1.65
7MO2	X-RAY DIFFRACTION	1.65
5CIT	X-RAY DIFFRACTION	1.75
5CIW	X-RAY DIFFRACTION	1.75
5CJ2	X-RAY DIFFRACTION	1.75
1I2M	X-RAY DIFFRACTION	1.76
4HAT	X-RAY DIFFRACTION	1.78
3GJ3	X-RAY DIFFRACTION	1.79
3GJ5	X-RAY DIFFRACTION	1.79
4HB2	X-RAY DIFFRACTION	1.8
4WVF	X-RAY DIFFRACTION	1.8
7CND	X-RAY DIFFRACTION	1.8
7MNR	X-RAY DIFFRACTION	1.8
7MNV	X-RAY DIFFRACTION	1.8
3GJ8	X-RAY DIFFRACTION	1.82
4HAW	X-RAY DIFFRACTION	1.9
4HAZ	X-RAY DIFFRACTION	1.9
3GJ7	X-RAY DIFFRACTION	1.93
6XJR	X-RAY DIFFRACTION	1.94
6XJS	X-RAY DIFFRACTION	1.94
7L5E	X-RAY DIFFRACTION	1.94
4HAU	X-RAY DIFFRACTION	2
4HAV	X-RAY DIFFRACTION	2
7MNU	X-RAY DIFFRACTION	2
9X7O	X-RAY DIFFRACTION	2
6NIF	X-RAY DIFFRACTION	2
6CIT	X-RAY DIFFRACTION	2.03

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-P62826-F1	89.09	0.71

Functional residue map

Curated UniProt residues grouped by drug-discovery relevance — catalytic, ligand-binding, modification, and mutation-validated positions. Source: UniProtKB sequence features.

Catalytic / active sites (1): 69 (essential for gtp hydrolysis)

Ligand- & substrate-binding residues (5): 150–152; 18–25; 36–42; 68; 122–125

Post-translational modifications (12): 2, 24, 37, 60, 71, 99, 134, 159, 159, 71, 71, 152

Mutagenesis-validated functional residues (14):

Position	Phenotype
19	blocks dna replication; when associated with l-69.
24	has low binding affinity for gtp and gdp. almost completely abolishes interaction with birc5.
24	has low binding affinity for gtp and gdp. decreases nuclear import of proteins and rna. stabilizes the interaction with
25	minor effect on the interaction with the alpha phosphate group of bound gtp.
37	mimics acetylation; enhances the nuclear export of rela/p65.
37	decreased acetylation.
39	abolishes steric hindrance that traps the essential q-69 in an unreactive position, and causes slow gtp hydrolysis in wi
69	strongly decreased gtpase activity. probably locked in the gtp-bound form. loss of interaction with nutf2. decreases nuc
69	unable to hydrolyze gtp. increases binding to birc5 and promotes exaggerated spindle formation.
70	strongly decreases the relase of bound gdp.
76	probable loss of interaction with nutf2. loss of transport to the nucleus.
134	loss of normal mitotic chromosome segregation and defective mitotic spindle orientation.
134	loss of normal mitotic chromosome segregation and formation of sister chromatid bridges.
211–216	no effect on gtpase activity. abolishes interaction with ranbp1.

Function

Pathways and Gene Ontology

Reactome pathways

8 pathways

ID	Pathway
R-HSA-165054	Rev-mediated nuclear export of HIV RNA
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-168333	NEP/NS2 Interacts with the Cellular Export Machinery
R-HSA-180746	Nuclear import of Rev protein
R-HSA-203927	MicroRNA (miRNA) biogenesis
R-HSA-5578749	Transcriptional regulation by small RNAs
R-HSA-6784531	tRNA processing in the nucleus
R-HSA-9615933	Postmitotic nuclear pore complex (NPC) reformation

MSigDB gene sets: 489 (showing top): GSE45365_CTRL_VS_MCMV_INFECTION_NK_CELL_DN, GNF2_CKS1B, PID_HDAC_CLASSI_PATHWAY, GOBP_CHROMOSOME_ORGANIZATION, GCM_MAP4K4, GOBP_RIBOSOME_BIOGENESIS, BORCZUK_MALIGNANT_MESOTHELIOMA_UP, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GCM_GSPT1, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, KAAB_FAILED_HEART_ATRIUM_DN, GOBP_CELLULAR_RESPONSE_TO_LIPID, GOBP_RESPONSE_TO_CORTICOSTEROID, GOBP_POSITIVE_REGULATION_OF_INTRACELLULAR_PROTEIN_TRANSPORT, MORF_UBE2I

GO Biological Process (25): ribosomal subunit export from nucleus (GO:0000054), ribosomal large subunit export from nucleus (GO:0000055), ribosomal small subunit export from nucleus (GO:0000056), mitotic sister chromatid segregation (GO:0000070), mitotic cell cycle (GO:0000278), DNA metabolic process (GO:0006259), protein import into nucleus (GO:0006606), protein export from nucleus (GO:0006611), mitotic spindle organization (GO:0007052), spermatid development (GO:0007286), viral process (GO:0016032), hippocampus development (GO:0021766), actin cytoskeleton organization (GO:0030036), protein-containing complex localization (GO:0031503), pre-miRNA export from nucleus (GO:0035281), positive regulation of protein import into nucleus (GO:0042307), GTP metabolic process (GO:0046039), cell division (GO:0051301), snRNA import into nucleus (GO:0061015), cellular response to mineralocorticoid stimulus (GO:0071389), protein localization to nucleolus (GO:1902570), glycolytic process (GO:0006096), nucleocytoplasmic transport (GO:0006913), intracellular protein localization (GO:0008104), protein transport (GO:0015031)

GO Molecular Function (19): magnesium ion binding (GO:0000287), chromatin binding (GO:0003682), RNA binding (GO:0003723), GTPase activity (GO:0003924), G protein activity (GO:0003925), GTP binding (GO:0005525), GDP binding (GO:0019003), protein domain specific binding (GO:0019904), protein-containing complex binding (GO:0044877), cadherin binding (GO:0045296), dynein intermediate chain binding (GO:0045505), protein heterodimerization activity (GO:0046982), importin-alpha family protein binding (GO:0061676), nucleotide binding (GO:0000166), nuclear export signal receptor activity (GO:0005049), protein binding (GO:0005515), hydrolase activity (GO:0016787), metal ion binding (GO:0046872), pre-miRNA binding (GO:0070883)

GO Cellular Component (19): chromatin (GO:0000785), male germ cell nucleus (GO:0001673), manchette (GO:0002177), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), nucleolus (GO:0005730), cytoplasm (GO:0005737), centriole (GO:0005814), cytosol (GO:0005829), membrane (GO:0016020), midbody (GO:0030496), protein-containing complex (GO:0032991), sperm flagellum (GO:0036126), melanosome (GO:0042470), RNA nuclear export complex (GO:0042565), recycling endosome (GO:0055037), extracellular exosome (GO:0070062)

Reactome top-level categories

Rollup of top-7 pathways:

Category	Pathways
Interactions of Rev with host cellular proteins	2
Gene Silencing by RNA	2
Late Phase of HIV Life Cycle	1
Metabolism of steroids	1
Export of Viral Ribonucleoproteins from Nucleus	1
tRNA processing	1
Nuclear Envelope (NE) Reassembly	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	7
nuclear export	3
binding	3
protein binding	3
ribosomal subunit export from nucleus	2
mitotic nuclear division	2
intracellular protein transport	2
guanyl ribonucleotide binding	2
nuclear lumen	2
intracellular membraneless organelle	2
ribosome localization	1
ribosome biogenesis	1
establishment of organelle localization	1
sister chromatid segregation	1
mitotic cell cycle process	1
cell cycle	1
nucleic acid metabolic process	1
protein localization to nucleus	1
import into nucleus	1
establishment of protein localization to organelle	1
mitotic cell cycle	1
spindle organization	1
microtubule cytoskeleton organization involved in mitosis	1
germ cell development	1
spermatid differentiation	1
biological_process	1
pallium development	1
limbic system development	1
anatomical structure development	1
cytoskeleton organization	1
actin filament-based process	1
macromolecule localization	1
RNA export from nucleus	1
miRNA-mediated post-transcriptional gene silencing	1
protein import into nucleus	1
regulation of protein import into nucleus	1
positive regulation of nucleocytoplasmic transport	1
positive regulation of intracellular protein transport	1
positive regulation of protein localization to nucleus	1
purine ribonucleotide metabolic process	1

Protein interactions and networks

STRING

0 interactions, top by confidence (×1000):

IntAct

740 interactions, top by confidence:

A	B	Type	Score
IKBKB	CHUK	psi-mi:“MI:0914”(association)	0.960
RCC1	RAN	psi-mi:“MI:0407”(direct interaction)	0.950
RAN	RCC1	psi-mi:“MI:0407”(direct interaction)	0.950
RAN	RCC1	psi-mi:“MI:0915”(physical association)	0.950
RAN	RCC1	psi-mi:“MI:0914”(association)	0.950
RCC1	RAN	psi-mi:“MI:0915”(physical association)	0.950
RAN	NUTF2	psi-mi:“MI:0915”(physical association)	0.890
NUTF2	RAN	psi-mi:“MI:0407”(direct interaction)	0.890
RAN	RANBP2	psi-mi:“MI:0407”(direct interaction)	0.860
KIF3A	KIF3B	psi-mi:“MI:0914”(association)	0.840
	RAN	psi-mi:“MI:0407”(direct interaction)	0.810
	RAN	psi-mi:“MI:0407”(direct interaction)	0.760
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710

BioGRID (789): RAN (Affinity Capture-MS), NUTF2 (Two-hybrid), RAN (Two-hybrid), RAN (Two-hybrid), RAN (Affinity Capture-Western), HERC5 (Affinity Capture-Western), RAN (Affinity Capture-MS), RAN (Affinity Capture-MS), RAN (Affinity Capture-MS), RAN (Affinity Capture-MS), RAN (Affinity Capture-MS), RAN (Affinity Capture-MS), RAN (Affinity Capture-MS), RAN (Affinity Capture-MS), Rangap1 (Far Western)

ESM2 similar proteins: A2WSI7, A2Y7R5, A2YEQ6, A8HN58, O17915, P28748, P32835, P32836, P33519, P38542, P38543, P38544, P38545, P38546, P38547, P38548, P41914, P41915, P41916, P41917, P41918, P41919, P42558, P52301, P54765, P54766, P62825, P62826, P62827, P62828, P79735, Q3T054, Q4R4M9, Q5R556, Q61820, Q69XM7, Q6FR65, Q6GL85, Q74ZA9, Q7F7I7

Diamond homologs: A2WSI7, A2Y7R5, A2YEQ6, H9BW96, O17915, O76742, O97572, P09527, P18067, P22127, P24408, P24409, P28748, P32835, P32836, P33519, P34139, P35288, P36411, P36864, P38542, P38543, P38544, P38545, P38546, P38547, P38548, P41914, P41915, P41916, P41917, P41918, P41919, P42558, P51149, P51150, P51151, P52301, P54765, P54766

SIGNOR signaling

7 interactions.

A	Effect	B	Mechanism
PLK1	up-regulates	RAN	phosphorylation
PAK4	up-regulates	RAN	phosphorylation
PAK4	unknown	RAN	phosphorylation
RAN	“up-regulates activity”	XPOT	binding
MYCBP2	“up-regulates activity”	RAN	“guanine nucleotide exchange factor”
RAN	“up-regulates activity”	XPO1	binding
SIRT7	“down-regulates activity”	RAN	deacetylation

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 154 IntAct physical interaction partners (hypergeometric vs the genome-wide background, BH-FDR, gene-set size 15–500, ranked by fold). A functional readout of the neighbourhood — distinct from this gene’s own memberships above, and biased toward well-studied / hub proteins, so read it as themes rather than proof.

Reactome pathways:

Pathway	Partners	Fold	FDR
NS1 Mediated Effects on Host Pathways	10	31.7×	3e-10
Transport of Ribonucleoproteins into the Host Nucleus	7	27.8×	1e-06
Postmitotic nuclear pore complex (NPC) reformation	6	27.2×	1e-05
Nuclear import of Rev protein	7	26.1×	1e-06
Vpr-mediated nuclear import of PICs	6	22.4×	3e-05
SUMOylation of SUMOylation proteins	6	21.8×	3e-05
Rev-mediated nuclear export of HIV RNA	6	21.1×	3e-05
IPs transport between nucleus and cytosol	5	21.1×	1e-04

GO biological processes:

GO term	Partners	Fold	FDR
NLS-bearing protein import into nucleus	8	58.4×	3e-10
protein import into nucleus	16	20.9×	5e-14
canonical NF-kappaB signal transduction	5	16.6×	3e-03
tumor necrosis factor-mediated signaling pathway	5	15.0×	4e-03
nucleosome assembly	6	7.7×	8e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

10 variants total. Per-class counts are floors (≥ shown; pagination cap):

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	1
Likely benign	0
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

925 predictions. Top by Δscore:

Variant	Effect	Δscore
12:130872123:GAAGG:G	donor_loss	1.0000
12:130872124:A:T	donor_gain	1.0000
12:130872124:AAGG:A	donor_loss	1.0000
12:130872125:AGGTA:A	donor_loss	1.0000
12:130872126:GGTA:G	donor_loss	1.0000
12:130872127:G:GA	donor_loss	1.0000
12:130872128:T:G	donor_loss	1.0000
12:130872834:A:AG	acceptor_gain	1.0000
12:130872835:G:GG	acceptor_gain	1.0000
12:130872835:GCTT:G	acceptor_gain	1.0000
12:130872910:G:GT	donor_gain	1.0000
12:130872910:GAA:G	donor_gain	1.0000
12:130872913:G:GG	donor_gain	1.0000
12:130872917:GTAG:G	donor_loss	1.0000
12:130872918:TAG:T	donor_loss	1.0000
12:130872919:AG:A	donor_loss	1.0000
12:130872920:GGT:G	donor_loss	1.0000
12:130872922:T:G	donor_loss	1.0000
12:130872997:TTTCA:T	acceptor_loss	1.0000
12:130872999:TCA:T	acceptor_loss	1.0000
12:130873001:A:AC	acceptor_loss	1.0000
12:130873001:A:AG	acceptor_gain	1.0000
12:130873002:G:GA	acceptor_gain	1.0000
12:130873002:G:GC	acceptor_loss	1.0000
12:130873002:GCC:G	acceptor_gain	1.0000
12:130873002:GCCA:G	acceptor_gain	1.0000
12:130873002:GCCAC:G	acceptor_gain	1.0000
12:130873129:G:A	donor_loss	1.0000
12:130873130:T:A	donor_loss	1.0000
12:130874544:A:AG	acceptor_gain	1.0000

AlphaMissense

1427 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
12:130872848:G:A	G17S	1.000
12:130872848:G:C	G17R	1.000
12:130872848:G:T	G17C	1.000
12:130872849:G:A	G17D	1.000
12:130872849:G:T	G17V	1.000
12:130872851:G:C	D18H	1.000
12:130872852:A:T	D18V	1.000
12:130872855:G:A	G19D	1.000
12:130872863:G:A	G22R	1.000
12:130872863:G:C	G22R	1.000
12:130872864:G:A	G22E	1.000
12:130872864:G:T	G22V	1.000
12:130872866:A:C	K23Q	1.000
12:130872867:A:T	K23I	1.000
12:130872868:A:C	K23N	1.000
12:130872868:A:T	K23N	1.000
12:130872870:C:T	T24M	1.000
12:130872884:C:A	R29S	1.000
12:130872885:G:C	R29P	1.000
12:130872902:T:C	F35L	1.000
12:130872903:T:C	F35S	1.000
12:130872903:T:G	F35C	1.000
12:130872904:T:A	F35L	1.000
12:130872904:T:G	F35L	1.000
12:130872914:T:C	Y39H	1.000
12:130873003:C:A	A41D	1.000
12:130873006:C:T	T42I	1.000
12:130873011:G:C	G44R	1.000
12:130873012:G:A	G44D	1.000
12:130873071:T:A	W64R	1.000

dbSNP variants (sampled 300 via entrez): RS1000496344 (12:130874054 G>A,T), RS1000657044 (12:130876232 C>G), RS1000708796 (12:130876447 A>C,G), RS1001226339 (12:130876231 C>A,T), RS1001271444 (12:130871845 G>A,C), RS1001688379 (12:130870787 C>T), RS1001719824 (12:130872175 C>T), RS1002147428 (12:130875443 C>G), RS1002221090 (12:130875015 G>A), RS1003286922 (12:130877272 A>C), RS1003359831 (12:130870676 T>C), RS1003362481 (12:130872566 C>A,G,T), RS1003964801 (12:130874974 A>G,T), RS1004015690 (12:130874793 T>C,G), RS1004662802 (12:130872031 C>G)

Disease associations

OMIM: gene MIM:601179 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

0 total (0 of 0 shown, HPO-id order):

GWAS associations

0 associations (top):

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (2): CHEMBL1741190 (SINGLE PROTEIN), CHEMBL3885569 (PROTEIN COMPLEX)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 2,395 (via chembl_molecule»patent_compound — counts attach to the compound, not the gene–compound relationship, so off-target/promiscuous molecules can dominate).

Molecule	Name	Phase	Patents
CHEMBL3301622	GILTERITINIB	4	2,395

PharmGKB: 1 entry (VIP=true, CPIC=false)

ChEMBL bioactivities

5 potent at pChembl≥5 of 5 total, top 5 by pChembl (potency: 10 = 0.1 nM, 6 = 1 µM).

pChembl	Type	Value	Unit	Molecule
6.94	Kd	115.9	nM	CHEMBL5653589
6.94	ED50	115.9	nM	CHEMBL5653589
6.12	Kd	759	nM	GILTERITINIB
5.37	Kd	4292	nM	CHEMBL3752910
5.37	ED50	4292	nM	CHEMBL3752910

PubChem BioAssay actives

3 with measured affinity, of 252 total; 3 most potent distinct compounds. Largely complementary to BindingDB; screening values are coarse (µM, 4 dp), so sub-nM hits tie at the floor.

Compound	Assay	Type	Value	Unit
4-methyl-3-[(2-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149189: Binding affinity to human RAN incubated for 45 mins by Kinobead based pull down assay	kd	0.1159	uM
Gilteritinib	1425153: Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by mass spectrometry.	kd	0.7590	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149189: Binding affinity to human RAN incubated for 45 mins by Kinobead based pull down assay	kd	4.2917	uM

CTD chemical–gene interactions

66 total (human), top 30 by PubMed support.

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, decreases expression	4
sodium arsenite	affects cotreatment, decreases expression, increases expression	4
bisphenol F	decreases expression, increases expression, affects cotreatment	2
Resveratrol	decreases expression	2
Benzo(a)pyrene	increases expression, increases methylation, affects methylation	2
Estradiol	decreases expression, affects expression, affects cotreatment	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Asbestos, Crocidolite	affects expression, increases expression	2
FR900359	decreases phosphorylation	1
TAK-243	decreases sumoylation	1
dicrotophos	decreases expression	1
uranyl acetate	affects expression	1
trichostatin A	decreases expression	1
beta-lapachone	increases expression	1
arsenite	increases reaction, affects binding	1
ochratoxin A	affects binding	1
epigallocatechin gallate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
chloropicrin	increases expression	1
K 7174	decreases expression	1
nutlin 3	affects cotreatment, increases secretion	1
belinostat	decreases expression	1
bisphenol B	increases expression	1
2-amino-14,16-dimethyloctadecan-3-ol	decreases expression	1
Grape Seed Proanthocyanidins	affects cotreatment, increases expression	1
bisphenol S	increases expression	1
(+)-JQ1 compound	decreases expression	1
bisphenol AF	increases expression	1
Rosiglitazone	decreases expression	1
Acetaminophen	decreases expression	1

ChEMBL screening assays

10 unique, capped per target: 9 binding, 1 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL3991866	Binding	Kinobeads (epsilon), multiple immobilized ATP-competitive broad spectrum kinase inhibitors, used to assess residual binding of ~300 proteins simultaneously from cell lysate in the presence of a compound. Quantitative readout performed by ma	The target landscape of clinical kinase drugs. — Science
CHEMBL1794461	Functional	PUBCHEM_BIOASSAY: qHTS Assay for Inhibitors of RanGTP induced Rango (Ran-regulated importin-beta cargo) - Importin beta complex dissociation. (Class of assay: confirmatory) [Related pubchem assays (depositor defined):AID540262]	PubChem BioAssay data set

Clinical trials (associated diseases)

0 trials via MONDO — disease-level, not drug-specific.