KPNB1

Summary

KPNB1 (karyopherin subunit beta 1, HGNC:6400) is a protein-coding gene on chromosome 17q21.32, encoding Importin subunit beta-1 (Q14974). Functions in nuclear protein import, either in association with an adapter protein, like an importin-alpha subunit, which binds to nuclear localization signals (NLS) in cargo substrates, or by acting as autonomous nuclear transport receptor. It is a common-essential gene (DepMap: required in 100.0% of cancer cell lines).

Nucleocytoplasmic transport, a signal- and energy-dependent process, takes place through nuclear pore complexes embedded in the nuclear envelope. The import of proteins containing a nuclear localization signal (NLS) requires the NLS import receptor, a heterodimer of importin alpha and beta subunits also known as karyopherins. Importin alpha binds the NLS-containing cargo in the cytoplasm and importin beta docks the complex at the cytoplasmic side of the nuclear pore complex. In the presence of nucleoside triphosphates and the small GTP binding protein Ran, the complex moves into the nuclear pore complex and the importin subunits dissociate. Importin alpha enters the nucleoplasm with its passenger protein and importin beta remains at the pore. Interactions between importin beta and the FG repeats of nucleoporins are essential in translocation through the pore complex. The protein encoded by this gene is a member of the importin beta family. Two transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 3837 — RefSeq curated summary.

At a glance

• GWAS associations: 33
• Clinical variants (ClinVar): 62 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_002265

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:6400
Approved symbol	KPNB1
Name	karyopherin subunit beta 1
Location	17q21.32
Locus type	gene with protein product
Status	Approved
Aliases	NTF97, IPOB, MGC2155, MGC2156, MGC2157, IMB1, Impnb, IPO1
Ensembl gene	ENSG00000108424
Ensembl biotype	protein_coding
OMIM	602738
Entrez	3837

Gene structure

Transcript identifiers

Ensembl transcripts: 29 — 20 protein_coding, 5 retained_intron, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000290158, ENST00000535458, ENST00000540627, ENST00000577875, ENST00000577918, ENST00000578718, ENST00000579901, ENST00000580019, ENST00000580158, ENST00000580573, ENST00000582097, ENST00000582126, ENST00000583013, ENST00000583648, ENST00000677036, ENST00000677341, ENST00000866804, ENST00000866805, ENST00000866806, ENST00000866807, ENST00000866808, ENST00000931899, ENST00000931900, ENST00000931901, ENST00000931902, ENST00000931903, ENST00000931904, ENST00000931905, ENST00000946082

RefSeq mRNA: 2 — MANE Select: NM_002265 NM_001276453, NM_002265

CCDS: CCDS11513, CCDS62228

Canonical transcript exons

ENST00000290158 — 22 exons

Exon	Start	End
ENSE00000924982	47663089	47663178
ENSE00000924983	47664159	47664269
ENSE00000924984	47665057	47665158
ENSE00000924985	47668186	47668410
ENSE00000924991	47676409	47676491
ENSE00000924992	47677020	47677127
ENSE00000924994	47678308	47678413
ENSE00000924995	47680020	47680134
ENSE00001043047	47669678	47669869
ENSE00001328366	47649919	47650284
ENSE00001343442	47682404	47685505
ENSE00003472002	47673018	47673165
ENSE00003475408	47678046	47678189
ENSE00003535900	47656860	47657060
ENSE00003587966	47652694	47652876
ENSE00003594181	47650386	47650444
ENSE00003599520	47680508	47680669
ENSE00003637145	47674638	47674782
ENSE00003658165	47670702	47670832
ENSE00003669808	47661119	47661178
ENSE00003684596	47658508	47658660
ENSE00003786528	47673490	47673561

Expression profiles

Bgee: expression breadth ubiquitous, 299 present calls, max score 99.28.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 180.3481 / max 2955.7527, expressed in 1829 samples.

FANTOM5 promoters (10 alternative TSS)

Promoter ID	TPM avg	Samples expressed
161359	131.2783	1828
161358	34.0585	1815
161362	4.5777	1552
161360	4.0539	1609
161361	2.1219	1348
161356	1.9520	822
161357	1.2759	701
161363	0.3768	187
161355	0.3434	166
208230	0.3097	137

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
buccal mucosa cell	CL:0002336	99.28	gold quality
ventricular zone	UBERON:0003053	98.94	gold quality
embryo	UBERON:0000922	98.57	gold quality
ganglionic eminence	UBERON:0004023	98.57	gold quality
cranial nerve II	UBERON:0000941	98.50	gold quality
secondary oocyte	CL:0000655	98.45	gold quality
stromal cell of endometrium	CL:0002255	98.42	gold quality
islet of Langerhans	UBERON:0000006	98.42	gold quality
tendon of biceps brachii	UBERON:0008188	98.42	gold quality
medial globus pallidus	UBERON:0002477	98.39	gold quality
vermiform appendix	UBERON:0001154	98.32	gold quality
middle temporal gyrus	UBERON:0002771	98.32	gold quality
adrenal tissue	UBERON:0018303	98.28	gold quality
Brodmann (1909) area 23	UBERON:0013554	98.26	gold quality
tendon	UBERON:0000043	98.25	gold quality
superficial temporal artery	UBERON:0001614	98.25	gold quality
caecum	UBERON:0001153	98.24	gold quality
calcaneal tendon	UBERON:0003701	98.21	gold quality
tonsil	UBERON:0002372	98.20	gold quality
pylorus	UBERON:0001166	98.17	gold quality
epithelium of mammary gland	UBERON:0003244	98.17	gold quality
smooth muscle tissue	UBERON:0001135	98.15	gold quality
mammary duct	UBERON:0001765	98.11	gold quality
globus pallidus	UBERON:0001875	98.11	gold quality
lymph node	UBERON:0000029	98.08	gold quality
trabecular bone tissue	UBERON:0002483	98.05	gold quality
lower lobe of lung	UBERON:0008949	97.88	gold quality
substantia nigra pars compacta	UBERON:0001965	97.82	gold quality
pancreatic ductal cell	CL:0002079	97.80	gold quality
blood	UBERON:0000178	97.80	gold quality

Single-cell (SCXA)

Detected in 4 experiment(s), a significant marker in 1.

Experiment	Marker?	Max mean expression
E-ANND-3	yes	9.77
E-MTAB-9689	no	836.30
E-MTAB-3929	no	803.18
E-CURD-89	no	321.11

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): EZH2, SREBF2, SRF

miRNA regulators (miRDB)

90 targeting KPNB1, 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-6867-5P	100.00	82.21	3464
HSA-MIR-4262	100.00	73.26	3931
HSA-MIR-5193	100.00	67.26	1744
HSA-MIR-6740-5P	100.00	65.64	932
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-27A-3P	99.98	72.13	2955
HSA-MIR-27B-3P	99.98	72.13	2955
HSA-MIR-9985	99.98	72.11	2939
HSA-MIR-5696	99.98	72.36	4487
HSA-MIR-96-5P	99.95	72.80	2140
HSA-MIR-101-3P	99.94	75.03	2230
HSA-MIR-9983-3P	99.94	71.48	3631
HSA-MIR-335-3P	99.93	73.36	4958
HSA-MIR-12133	99.92	71.82	2006
HSA-MIR-1305	99.91	71.43	3443
HSA-MIR-1271-5P	99.91	71.99	1972
HSA-MIR-6809-3P	99.91	71.45	3814
HSA-MIR-4697-3P	99.89	67.09	1123
HSA-MIR-129-5P	99.88	70.26	3273
HSA-MIR-5003-3P	99.85	69.29	2517
HSA-MIR-4447	99.85	67.81	2900
HSA-MIR-629-3P	99.85	67.99	1875
HSA-MIR-5010-3P	99.83	70.60	2357
HSA-MIR-4668-5P	99.79	70.58	3782
HSA-MIR-498-5P	99.76	69.64	1807
HSA-MIR-4446-5P	99.72	69.19	2544
HSA-MIR-1825	99.72	68.11	1089

Functional genomics

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

Literature-anchored findings (GeneRIF, showing 40)

• nuclear import of the HPV16 E6 oncoprotein in digitonin-permeabilized HeLa cells could be mediated by Kap beta1 (PMID:12551970)
• XCTK2 binding to microtubules inhibited in the presence of importin alpha and beta (PMID:13679510)
• Importin alpha/beta-mediated nuclear import machinery is regulated in a cell cycle-dependent manner through the modulation of interaction modes between importins alpha and beta. (PMID:15194443)
• This study shows a direct role of importin beta in control of mitotic spindle pole organization in human cells (PMID:15572412)
• Inhibition by Impbeta results from depletion nuclear RanGTP, and, in support of this mechanism, expression of mRFP-Ran reversed the inhibition. (PMID:15795315)
• These data suggest the importance of receptor endocytosis, endosomal sorting machinery, interaction with importins alpha1/beta1, and exportin CRM1 in EGFR nuclear-cytoplasmic trafficking. (PMID:16552725)
• These results show that maximum nucleocytoplasmic transport velocities can be modulated by at least approximately 10-fold by the importin beta concentration and hence suggest a potential mechanism for regulating the speed of cargo traffic across the NE. (PMID:16982803)
• dengue virus nonstructural protein 5 nuclear localization through its importin alpha/beta-recognized nuclear localization sequences is integral to viral infection (PMID:17537211)
• SARS-COV ORF6 protein is localized to the endoplasmic reticulum (ER)/Golgi membrane in infected cells, where it binds to and disrupts nuclear import complex formation by tethering karyopherin alpha 2 and karyopherin beta 1 to the membrane. (PMID:17596301)
• Data show that a novel Crumbs3 isoform regulates cell division and ciliogenesis via importin beta1 interactions. (PMID:17646395)
• study found binding interactions with karyopherin-beta1 caused FG domains of nucleoporin Nup153 to collapse into compact molecular conformations; reversible collapse of the FG domains may play an important role in regulating nucleocytoplasmic transport (PMID:17916694)
• crystal structure of Imp beta (127-876) in complex SPN1 (1-65) at 2.8-A resolution reveals that Imp beta adopts an open conformation, which is unique for a functional Imp beta/cargo complex, and resembles the conformation of the Imp beta/RanGTP complex (PMID:18028944)
• importins alpha5 and beta1 associate with Nrf2, an interaction that was blocked by the nuclear import inhibitor SN50 (PMID:18238777)
• Crm1, Kpnbeta1 and Kpnalpha2 are overexpressed in cervical cancer and inhibiting the expression of Crm1 and Kpnbeta1, not Kpnalpha2, induces cancer cell death (PMID:19117056)
• replacement of the cap-binding complex by eukaryotic translation initiation factor 4E is promoted by importin beta (IMPbeta) (PMID:19884259)
• [review] Recognition and shuttling of calcineurin into the nucleus by importin-beta requires the nuclear localization sequence of the region spanning amino acids 172-183 of calcineurin A beta. (PMID:19925438)
• Results demonstrate that PP2A-B55alpha and importin-beta1 cooperate in the regulation of postmitotic assembly mechanisms in human cells. (PMID:20711181)
• The mammalian E1 subunits can be imported separately, identify nuclear localization signals (NLSs) in Aos1 and in Uba2, and demonstrate that their import is mediated by importin alpha/beta in vitro and in intact cells. (PMID:21209321)
• Importin beta interacts with the NFAT-tubulin alpha complex rather than NFAT or tubulin alpha alone, resulting in cotranslocation of NFAT and tubulin alpha into the nucleus. (PMID:21278340)
• study defines importin-alpha/importin-beta1/Ran as the molecular mechanism by which STAT3 traffics to the nucleus (PMID:21625522)
• [review] The cellular functions of Ran are mediated by RanGTP interactions with nuclear transport receptors related to importin beta and depend on the existence of chromosome-centered RanGTP gradient. (PMID:21630149)
• Findings suggest that the importin beta1-mediated nuclear localization of DR5 limits the DR5/TRAIL-induced cell death of human tumor cells and thus can be a novel target to improve cancer therapy with recombinant TRAIL and anti-DR5 antibodies. (PMID:22020938)
• Findings suggest that the deregulated activity of E2F in cancer cells causes increased activation of the Kpnbeta1 and Kpnalpha2 promoters, leading to elevated levels of these proteins, and ultimately impacting the cancer phenotype. (PMID:22125623)
• LRRC59 facilitates transport of cytosolic FGF1 through nuclear pores by interaction with Kpns and movement of LRRC59 along the ER and NE membranes (PMID:22321063)
• Nuclear translocation of Wilms’ tumour protein involves importins alpha and beta, and a nuclear localisation signal in the third zinc finger (PMID:22415091)
• Identification of a karyopherin beta1/beta2 proline-tyrosine nuclear localization signal in huntingtin protein. (PMID:23012356)
• Data show that five genes CKAP5, KPNB1, RAN, TPX2 and KIF11 were shown to be essential for tumor cell survival in both head and neck squamous cell carcinoma (HNSCC)and non-small cell lung cancer (NSCLC), but most particularly in HNSCC. (PMID:23444224)
• The role of Kpnbeta1 in cancer is only now being elucidated, and recent work points to its potential usefulness as an anti-cancer target. (PMID:23557333)
• Knockdown of KPNB1 reduced the amount of nuclear p65 following TNF stimulation. KPNB1 binding to p65 is NLS dependent. (PMID:23906023)
• we report that the EZH2-miR-30d-KPNB1 signalling pathway is critical for malignant peripheral nerve sheath tumour cell survival in vitro and tumourigenicity in vivo (PMID:24132643)
• the inhibition of endogenous Kpnbeta1 in cervical cancer cells results in a significant increase in mitotic abnormalities and a prolonged mitotic arrest. (PMID:24398670)
• Although there are many kinds of C2H2-type ZFs which have the same fold as Snail, nuclear import by direct recognition of importin beta is observed in a limited number of C2H2-type zinc-finger proteins such as Snail (PMID:24699649)
• This work extends published observations on SAMHD1 nuclear localization to a natural cell type for HIV-1 infection and identifies KPNA2/KPNB1 as cellular proteins important for SAMHD1 nuclear import. (PMID:24712655)
• These data reveal an emergent Kap-centric barrier mechanism that may underlie mechanistic and kinetic control in the nuclear pore complex. (PMID:24739174)
• Ei24 can bind specifically to IMPbeta1 and IMPalpha2 to impede their normal role in nuclear import. (PMID:24821838)
• Data suggest nuclear entry of GLI1 (glioma-associated oncogene homolog, a zinc finger protein) is regulated by unique mechanism via mutually exclusive binding by its nuclear import factor IMB1 (importin B1) and SuFu (suppressor of fused protein). (PMID:24854174)
• The results here establish for the first time that intracellular calcium modulates conventional nuclear import through direct effects on the nuclear transport machinery. (PMID:24953690)
• ARTD15 plays role in nucleocytoplasmic shuttling, through karyopherin-beta1 mono-ADP-ribosylation. [review] (PMID:25037261)
• ARHI competes with RanGTPase and interacts with importin beta via basic-acidic patch interaction, which leads to inhibition of STAT3 translocation. (PMID:25499977)
• Importin beta1 mediates the translocation of NF-kappaB into the nuclei of myeloma cells, thereby regulating proliferation and blocking apoptosis, which provides new insights for targeted myeloma therapies. (PMID:25643631)

Cross-species orthologs

5 orthologs

Organism	Symbol	Gene ID
danio_rerio	kpnb1	ENSDARG00000104889
mus_musculus	Kpnb1	ENSMUSG00000001440
rattus_norvegicus	Kpnb1	ENSRNOG00000009275
drosophila_melanogaster	Fs(2)Ket	FBGN0262743
caenorhabditis_elegans	imb-1	WBGENE00002075

Paralogs (5): IPO5 (ENSG00000065150), TNPO1 (ENSG00000083312), TNPO2 (ENSG00000105576), RANBP6 (ENSG00000137040), IPO4 (ENSG00000196497)

Protein

Protein identifiers

Importin subunit beta-1 — Q14974 (reviewed: Q14974)

Alternative names: Importin-90, Karyopherin subunit beta-1, Nuclear factor p97, Pore targeting complex 97 kDa subunit

All UniProt accessions (6): Q14974, J3KS06, J3KTM9, J3QKQ5, J3QR48, J3QRG4

UniProt curated annotations — full annotation on UniProt →

Function. Functions in nuclear protein import, either in association with an adapter protein, like an importin-alpha subunit, which binds to nuclear localization signals (NLS) in cargo substrates, or by acting as autonomous nuclear transport receptor. Acting autonomously, serves itself as NLS receptor. Docking of the importin/substrate complex to the nuclear pore complex (NPC) is mediated by KPNB1 through binding to nucleoporin FxFG repeats and the complex is subsequently translocated through the pore by an energy requiring, Ran-dependent mechanism. At the nucleoplasmic side of the NPC, Ran binds to importin-beta and the three components separate and importin-alpha and -beta are re-exported from the nucleus to the cytoplasm where GTP hydrolysis releases Ran from importin. The directionality of nuclear import is thought to be conferred by an asymmetric distribution of the GTP- and GDP-bound forms of Ran between the cytoplasm and nucleus. Mediates autonomously the nuclear import of ribosomal proteins RPL23A, RPS7 and RPL5. In association with IPO7, mediates the nuclear import of H1 histone. In vitro, mediates nuclear import of H2A, H2B, H3 and H4 histones. Imports MRTFA, SNAI1 and PRKCI into the nucleus. (Microbial infection) In case of HIV-1 infection, binds and mediates the nuclear import of HIV-1 Rev.

Subunit / interactions. Forms a complex with an importin alpha subunit. Interacts with XPO1. Forms a heterodimer with IPO7. The KPNB1/IPO7 heterodimer interacts with H1 histone. Interacts with SNUPN. Interacts with H2A, H2B, H3 and H4 histones. Component of an import snRNP complex composed of KPNB1, SNUPN, SMN1 and ZNF259. Component of a nuclear export receptor complex composed of KPNB1, Ran, SNUPN and XPO1. Interacts with SRY. Interacts with PRKCI/atypical protein kinase C iota. Interacts with KPNA2. Interacts with KPNA7. Interacts with SNAI1 (via zinc fingers) and SNAI2 (via zinc fingers). Interacts with SLC35G1 and STIM1. Interacts with DCAF8. Interacts with RAN. Interacts with NUMA1 (via C-terminus); this interaction is inhibited by RanGTP. Interacts with ZBED1/hDREF; required for nuclear import of ZBED1/hDREF. Interacts with SRP19. Interacts with RPL23A (via BIB domain), RPS7 and RPL5. (Microbial infection) Interacts with HIV-1 Rev and Tat. (Microbial infection) Interacts with HTLV-1 Rex. (Microbial infection) Interacts with human respiratory syncytial virus (HRSV) matrix protein; this interaction mediates nuclear import of the matrix protein early during infection. (Microbial infection) Part of a tetrameric complex composed of CRM1, importin alpha/beta dimer and the Venezuelan equine encephalitis virus (VEEV) capsid; this complex blocks the receptor-mediated transport through the nuclear pore.

Subcellular location. Cytoplasm. Nucleus envelope.

Post-translational modifications. Mono-ADP-ribosylated by PARP16.

Similarity. Belongs to the importin beta family. Importin beta-1 subfamily.

Isoforms (2)

UniProt ID	Names	Canonical?
Q14974-1	1	yes
Q14974-2	2

RefSeq proteins (2): NP_001263382, NP_002256* (*=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR000225	Armadillo	Repeat
IPR001494	Importin-beta_N	Domain
IPR011989	ARM-like	Homologous_superfamily
IPR016024	ARM-type_fold	Homologous_superfamily
IPR021133	HEAT_type_2	Repeat
IPR040122	Importin_beta	Family
IPR058584	IMB1_TNPO1-like_TPR	Domain

Pfam: PF03810, PF13513, PF25574

UniProt features (111 total): helix 56, repeat 19, strand 10, turn 10, modified residue 5, region of interest 3, sequence conflict 3, mutagenesis site 2, chain 1, domain 1, splice variant 1

Structure

Experimental structures (PDB)

23 structures.

PDB	Method	Resolution (Å)
1IBR	X-RAY DIFFRACTION	2.3
1QGR	X-RAY DIFFRACTION	2.3
2P8Q	X-RAY DIFFRACTION	2.35
1QGK	X-RAY DIFFRACTION	2.5
3W5K	X-RAY DIFFRACTION	2.6
9N85	ELECTRON MICROSCOPY	2.6
1F59	X-RAY DIFFRACTION	2.8
1O6O	X-RAY DIFFRACTION	2.8
1O6P	X-RAY DIFFRACTION	2.8
2QNA	X-RAY DIFFRACTION	2.84
1M5N	X-RAY DIFFRACTION	2.9
3LWW	X-RAY DIFFRACTION	3.15
2Q5D	X-RAY DIFFRACTION	3.2
9BFC	ELECTRON MICROSCOPY	3.2
9YB5	ELECTRON MICROSCOPY	3.2
9BAW	ELECTRON MICROSCOPY	3.3
9N86	ELECTRON MICROSCOPY	3.3
9N87	ELECTRON MICROSCOPY	3.4
9B4Y	ELECTRON MICROSCOPY	3.74
8GCN	ELECTRON MICROSCOPY	3.95
6N88	ELECTRON MICROSCOPY	6.2
9QEJ	ELECTRON MICROSCOPY	6.2
6N89	ELECTRON MICROSCOPY	7.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q14974-F1	94.81	0.89

Functional residue map

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

Post-translational modifications (5): 1, 12, 211, 835, 867

Mutagenesis-validated functional residues (2):

Position	Phenotype
178	largely reduced binding to fxfg repeats and reduced nuclear import.
178	loss of binding to fxfg repeats and reduced nuclear import.

Function

Pathways and Gene Ontology

Reactome pathways

49 pathways

ID	Pathway
R-HSA-1169408	ISG15 antiviral mechanism
R-HSA-140342	Apoptosis induced DNA fragmentation
R-HSA-1655829	Regulation of cholesterol biosynthesis by SREBP (SREBF)
R-HSA-168271	Transport of Ribonucleoproteins into the Host Nucleus
R-HSA-168276	NS1 Mediated Effects on Host Pathways
R-HSA-180746	Nuclear import of Rev protein
R-HSA-2995383	Initiation of Nuclear Envelope (NE) Reformation
R-HSA-6798695	Neutrophil degranulation
R-HSA-68616	Assembly of the ORC complex at the origin of replication
R-HSA-909733	Interferon alpha/beta signaling
R-HSA-9615933	Postmitotic nuclear pore complex (NPC) reformation
R-HSA-9636249	Inhibition of nitric oxide production
R-HSA-9692916	SARS-CoV-1 activates/modulates innate immune responses
R-HSA-9828806	Maturation of hRSV A proteins
R-HSA-9918432	Maturation of DENV proteins
R-HSA-109581	Apoptosis
R-HSA-1169410	Antimicrobial mechanism of IFN-stimulated genes
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1430728	Metabolism
R-HSA-162906	HIV Infection
R-HSA-162909	Host Interactions of HIV factors
R-HSA-1640170	Cell Cycle
R-HSA-1643685	Disease
R-HSA-168249	Innate Immune System
R-HSA-168255	Influenza Infection
R-HSA-168256	Immune System
R-HSA-177243	Interactions of Rev with host cellular proteins
R-HSA-2555396	Mitotic Metaphase and Anaphase
R-HSA-2995410	Nuclear Envelope (NE) Reassembly
R-HSA-5357801	Programmed Cell Death

MSigDB gene sets: 452 (showing top): E2F_Q4, GOBP_CHROMOSOME_ORGANIZATION, REACTOME_DNA_REPLICATION, REACTOME_APOPTOSIS_INDUCED_DNA_FRAGMENTATION, E2F_Q4_01, HORIUCHI_WTAP_TARGETS_DN, GOBP_CYTOPLASMIC_MICROTUBULE_ORGANIZATION, REACTOME_INNATE_IMMUNE_SYSTEM, PAX4_01, CCAWYNNGAAR_UNKNOWN, GOBP_INTRACELLULAR_PROTEIN_TRANSPORT, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOCC_SECRETORY_GRANULE, CMYB_01, GOBP_SPINDLE_LOCALIZATION

GO Biological Process (14): RNA import into nucleus (GO:0006404), protein import into nucleus (GO:0006606), NLS-bearing protein import into nucleus (GO:0006607), ribosomal protein import into nucleus (GO:0006610), mitotic chromosome movement towards spindle pole (GO:0007079), mitotic metaphase chromosome alignment (GO:0007080), astral microtubule organization (GO:0030953), establishment of mitotic spindle localization (GO:0040001), positive regulation of cholesterol biosynthetic process (GO:0045542), mitotic spindle assembly (GO:0090307), intracellular protein transport (GO:0006886), protein transport (GO:0015031), positive regulation of hippo signaling (GO:0035332), positive regulation of DNA-templated transcription (GO:0045893)

GO Molecular Function (10): RNA binding (GO:0003723), nuclear localization sequence binding (GO:0008139), zinc ion binding (GO:0008270), enzyme binding (GO:0019899), protein domain specific binding (GO:0019904), small GTPase binding (GO:0031267), Hsp90 protein binding (GO:0051879), nuclear import signal receptor activity (GO:0061608), importin-alpha family protein binding (GO:0061676), protein binding (GO:0005515)

GO Cellular Component (16): extracellular region (GO:0005576), nucleus (GO:0005634), nuclear envelope (GO:0005635), nuclear pore (GO:0005643), nucleoplasm (GO:0005654), cytoplasm (GO:0005737), cytosol (GO:0005829), cytoplasmic stress granule (GO:0010494), membrane (GO:0016020), nuclear membrane (GO:0031965), specific granule lumen (GO:0035580), NLS-dependent protein nuclear import complex (GO:0042564), extracellular exosome (GO:0070062), endoplasmic reticulum tubular network (GO:0071782), ficolin-1-rich granule lumen (GO:1904813), protein-containing complex (GO:0032991)

Reactome top-level categories

Rollup of top-16 pathways:

Category	Pathways
Influenza Infection	2
Nuclear Envelope (NE) Reassembly	2
Interferon Signaling	2
Antimicrobial mechanism of IFN-stimulated genes	1
Apoptotic execution phase	1
Metabolism of steroids	1
Interactions of Rev with host cellular proteins	1
Innate Immune System	1
Assembly of the pre-replicative complex	1
Suppression of phagosomal maturation	1
SARS-CoV-1-host interactions	1
Respiratory syncytial virus (RSV) genome replication, transcription and translation	1
Dengue Virus Genome Translation and Replication	1
Programmed Cell Death	1
Immune System	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	5
import into nucleus	3
mitotic sister chromatid segregation	3
mitotic cell cycle	3
protein binding	3
protein import into nucleus	2
mitotic cell cycle process	2
intracellular protein localization	2
nucleus	2
nuclear envelope	2
RNA transport	1
intracellular protein transport	1
protein localization to nucleus	1
establishment of protein localization to organelle	1
chromosome movement towards spindle pole	1
metaphase chromosome alignment	1
spindle organization	1
cytoplasmic microtubule organization	1
establishment of spindle localization	1
microtubule cytoskeleton organization involved in mitosis	1
cholesterol biosynthetic process	1
regulation of cholesterol biosynthetic process	1
positive regulation of cholesterol metabolic process	1
positive regulation of sterol biosynthetic process	1
positive regulation of alcohol biosynthetic process	1
mitotic spindle organization	1
spindle assembly	1
mitotic nuclear division	1
protein transport	1
intracellular transport	1
transport	1
establishment of protein localization	1
hippo signaling	1
regulation of hippo signaling	1
positive regulation of intracellular signal transduction	1
DNA-templated transcription	1
regulation of DNA-templated transcription	1
positive regulation of RNA biosynthetic process	1
nucleic acid binding	1
signal sequence receptor activity	1

Protein interactions and networks

STRING

3112 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
KPNB1	KPNA1	P52294	983
KPNB1	KPNA2	P52292	966
KPNB1	KPNA5	O15131	887
KPNB1	KPNA4	O00629	886
KPNB1	KPNA6	O60684	882
KPNB1	IPO11	Q9UI26	843
KPNB1	KPNA3	O00505	836
KPNB1	IQGAP1	P46940	833
KPNB1	NUP153	P49790	799
KPNB1	XPO1	O14980	794
KPNB1	CSE1L	P55060	790
KPNB1	ZBED1	O96006	761
KPNB1	HSPA9	P30036	748
KPNB1	RANGAP1	P46060	747
KPNB1	PSMD11	O00231	728

IntAct

459 interactions, top by confidence:

A	B	Type	Score
EIF4ENIF1	EIF4E	psi-mi:“MI:0914”(association)	0.940
KPNB1	KPNA2	psi-mi:“MI:0407”(direct interaction)	0.930
KPNB1	KPNA2	psi-mi:“MI:0915”(physical association)	0.930
NUP98	RAE1	psi-mi:“MI:0914”(association)	0.930
NUP153	KPNB1	psi-mi:“MI:0914”(association)	0.820
KPNB1	NUP153	psi-mi:“MI:0407”(direct interaction)	0.820
KPNB1	NUP153	psi-mi:“MI:0915”(physical association)	0.820
KPNB1	KPNA4	psi-mi:“MI:0407”(direct interaction)	0.800
DICER1	PRKRA	psi-mi:“MI:0914”(association)	0.800
KPNA2	NUP153	psi-mi:“MI:0914”(association)	0.790
KPNB1	KPNA1	psi-mi:“MI:0407”(direct interaction)	0.760
PPP1CB	CCDC85C	psi-mi:“MI:0914”(association)	0.750
PPP1CB	CCDC85C	psi-mi:“MI:2364”(proximity)	0.750
PPP1CC	CCDC85C	psi-mi:“MI:0914”(association)	0.740
PPP1CC	CCDC85C	psi-mi:“MI:2364”(proximity)	0.740
DLGAP5	KPNB1	psi-mi:“MI:0914”(association)	0.730
CFTR	XPO1	psi-mi:“MI:0914”(association)	0.710
CFTR	ESYT2	psi-mi:“MI:0914”(association)	0.710
KPNB1	KPNA3	psi-mi:“MI:0407”(direct interaction)	0.690
KPNB1	KPNA6	psi-mi:“MI:0407”(direct interaction)	0.690
MTA2	KPNA2	psi-mi:“MI:0914”(association)	0.690
MAPK7	PFDN6	psi-mi:“MI:0914”(association)	0.640
NCBP2	KPNA3	psi-mi:“MI:0914”(association)	0.640

BioGRID (885): KPNB1 (Affinity Capture-MS), KPNB1 (Affinity Capture-MS), KPNB1 (Two-hybrid), KPNB1 (Affinity Capture-MS), KPNB1 (Affinity Capture-MS), KPNB1 (Affinity Capture-MS), KPNB1 (Affinity Capture-MS), KPNB1 (Affinity Capture-MS), KPNB1 (Reconstituted Complex), KPNB1 (Affinity Capture-MS), KPNB1 (Affinity Capture-MS), KPNB1 (Affinity Capture-MS), KPNB1 (Reconstituted Complex), RAN (Reconstituted Complex), NUP100 (Reconstituted Complex)

ESM2 similar proteins: A0JN27, C9WPN6, F1LTR1, F1QGW6, O14787, O14980, O15294, P17427, P18484, P20461, P41091, P52296, P52297, P56558, P61201, P61202, P61203, P70168, P81436, P81795, Q13888, Q14974, Q27HV0, Q28D01, Q2KHU8, Q2TBV5, Q2VIR3, Q3SYU7, Q5F398, Q5HZM6, Q5R797, Q5RIC0, Q5SP67, Q5ZHS1, Q5ZMS3, Q6IQT4, Q6IR75, Q6NVL5, Q6P1K8, Q6P5F9

Diamond homologs: O13864, O18388, P52296, P52297, P70168, Q06142, Q14974, Q9FJD4, O60100

SIGNOR signaling

4 interactions.

A	Effect	B	Mechanism
KPNB1	up-regulates	SMAD3	relocalization
KPNA1	“up-regulates activity”	KPNB1	binding
KPNB1	“up-regulates activity”	“ISGF3 complex”	relocalization
ORF6	“down-regulates activity”	KPNB1	relocalization

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 198 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	13	29.0×	1e-13
Transport of the SLBP independent Mature mRNA	11	28.0×	2e-11
Transport of the SLBP Dependant Mature mRNA	11	27.3×	2e-11
Rev-mediated nuclear export of HIV RNA	11	27.3×	2e-11
NEP/NS2 Interacts with the Cellular Export Machinery	10	27.0×	2e-10
Nuclear import of Rev protein	10	26.2×	3e-10
Transport of Ribonucleoproteins into the Host Nucleus	9	25.1×	5e-09
IPs transport between nucleus and cytosol	8	23.8×	5e-08

GO biological processes:

GO term	Partners	Fold	FDR
RNA export from nucleus	7	42.3×	5e-08
NLS-bearing protein import into nucleus	8	41.4×	6e-09
nucleocytoplasmic transport	9	22.8×	5e-08
protein import into nucleus	24	22.3×	9e-23
mRNA export from nucleus	10	19.1×	5e-08
tumor necrosis factor-mediated signaling pathway	6	12.8×	9e-04
protein dephosphorylation	8	11.4×	1e-04
MAPK cascade	7	6.9×	7e-03

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	30
Likely benign	1
Benign	1

Top pathogenic / likely-pathogenic (0)

SpliceAI

2615 predictions. Top by Δscore:

Variant	Effect	Δscore
17:47650281:CCCG:C	donor_loss	1.0000
17:47650283:CG:C	donor_loss	1.0000
17:47650284:GG:G	donor_loss	1.0000
17:47650285:G:GG	donor_gain	1.0000
17:47650285:GTAGG:G	donor_loss	1.0000
17:47652689:A:AG	acceptor_gain	1.0000
17:47652690:A:G	acceptor_gain	1.0000
17:47652691:CAGC:C	acceptor_loss	1.0000
17:47652692:A:AC	acceptor_loss	1.0000
17:47652692:A:AG	acceptor_gain	1.0000
17:47652693:G:GG	acceptor_gain	1.0000
17:47652693:GC:G	acceptor_gain	1.0000
17:47652693:GCC:G	acceptor_gain	1.0000
17:47652693:GCCC:G	acceptor_gain	1.0000
17:47652693:GCCCA:G	acceptor_gain	1.0000
17:47652872:ACTAT:A	donor_gain	1.0000
17:47652873:CTAT:C	donor_gain	1.0000
17:47652874:TAT:T	donor_gain	1.0000
17:47652875:AT:A	donor_gain	1.0000
17:47652875:ATG:A	donor_loss	1.0000
17:47652876:TG:T	donor_loss	1.0000
17:47652877:G:GG	donor_gain	1.0000
17:47652877:G:T	donor_loss	1.0000
17:47652878:T:TG	donor_loss	1.0000
17:47652879:GAGTA:G	donor_loss	1.0000
17:47652880:AGTAA:A	donor_loss	1.0000
17:47652881:G:GG	donor_gain	1.0000
17:47656858:A:C	acceptor_loss	1.0000
17:47657031:G:GT	donor_gain	1.0000
17:47657056:A:G	donor_gain	1.0000

AlphaMissense

5753 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
17:47650264:T:A	L7H	1.000
17:47650264:T:C	L7P	1.000
17:47652713:T:C	L40P	1.000
17:47652725:T:C	L44P	1.000
17:47652760:G:C	A56P	1.000
17:47652763:G:C	A57P	1.000
17:47652764:C:A	A57D	1.000
17:47652766:G:C	G58R	1.000
17:47652767:G:A	G58D	1.000
17:47652770:T:C	L59P	1.000
17:47652778:A:G	K62E	1.000
17:47652780:G:C	K62N	1.000
17:47652780:G:T	K62N	1.000
17:47652832:T:A	W80R	1.000
17:47652832:T:C	W80R	1.000
17:47656903:C:A	A109D	1.000
17:47656927:C:A	A117D	1.000
17:47656953:T:A	W126R	1.000
17:47656953:T:C	W126R	1.000
17:47656975:T:C	L133P	1.000
17:47657034:G:C	A153P	1.000
17:47657040:G:C	G155R	1.000
17:47657041:G:A	G155D	1.000
17:47657041:G:T	G155V	1.000
17:47657050:G:A	C158Y	1.000
17:47657051:C:G	C158W	1.000
17:47658545:T:A	L174Q	1.000
17:47658545:T:C	L174P	1.000
17:47658554:T:A	I177K	1.000
17:47658554:T:G	I177R	1.000

dbSNP variants (sampled 300 via entrez): RS1000313197 (17:47667686 T>C), RS1000364419 (17:47654382 C>T), RS1000367066 (17:47667333 A>G), RS1000384439 (17:47670540 ATAGT>A), RS1000600540 (17:47662232 C>T), RS1000645120 (17:47685258 T>G), RS1000675490 (17:47660836 A>G), RS1000710123 (17:47669284 G>A), RS1000727005 (17:47671829 C>T), RS1000754301 (17:47668881 G>A), RS1000774278 (17:47676993 G>C,T), RS1000951413 (17:47662584 A>G), RS1001214037 (17:47676091 C>T), RS1001309374 (17:47653630 A>G,T), RS1001361851 (17:47649803 C>A,G,T)

Disease associations

OMIM: gene MIM:602738 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

33 associations (top):

Study	Trait	p-value
GCST001341_8	Multiple sclerosis	1.000000e-07
GCST002690_12	Very long-chain saturated fatty acid levels (fatty acid 20:0)	4.000000e-07
GCST002762_18	Optic cup area	2.000000e-08
GCST002762_3	Optic cup area	2.000000e-08
GCST005951_16	Body mass index	4.000000e-08
GCST006611_60	HDL cholesterol	4.000000e-08
GCST007638_1	Glycine levels	4.000000e-11
GCST007931_57	Medication use (HMG CoA reductase inhibitors)	4.000000e-09
GCST008070_106	HDL cholesterol levels	2.000000e-06
GCST008074_60	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-06
GCST008074_80	Triglyceride levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	1.000000e-07
GCST008075_195	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	2.000000e-07
GCST008075_82	HDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	7.000000e-08
GCST008076_40	Triglyceride levels	9.000000e-08
GCST008077_75	LDL cholesterol levels	2.000000e-08
GCST008078_67	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	6.000000e-22
GCST008078_9	LDL cholesterol levels x alcohol consumption (regular vs non-regular drinkers) interaction (2df)	3.000000e-16
GCST008079_139	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-24
GCST008079_14	LDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	3.000000e-17
GCST008083_109	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-07
GCST008083_127	Triglyceride levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	6.000000e-09
GCST008084_172	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	7.000000e-08
GCST008084_99	HDL cholesterol levels x alcohol consumption (drinkers vs non-drinkers) interaction (2df)	5.000000e-08
GCST008085_178	HDL cholesterol levels in current drinkers	4.000000e-07
GCST008085_91	HDL cholesterol levels in current drinkers	2.000000e-08
GCST008086_58	LDL cholesterol levels in current drinkers	2.000000e-11
GCST008086_95	LDL cholesterol levels in current drinkers	2.000000e-08
GCST008087_108	Triglyceride levels in current drinkers	6.000000e-06
GCST008087_28	Triglyceride levels in current drinkers	1.000000e-07
GCST008551_26	Simvastatin-induced myopathy	6.000000e-06

EFO canonical traits (10, from GWAS)

EFO ID	Trait name
EFO:0006796	very long-chain saturated fatty acid measurement
EFO:0004340	body mass index
EFO:0004612	high density lipoprotein cholesterol measurement
EFO:0009767	glycine measurement
EFO:0009932	HMG CoA reductase inhibitor use measurement
EFO:0004530	triglyceride measurement
EFO:0004611	low density lipoprotein cholesterol measurement
EFO:0004329	alcohol drinking
EFO:0004574	total cholesterol measurement
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (3): CHEMBL1741199 (SINGLE PROTEIN), CHEMBL3885569 (PROTEIN COMPLEX), CHEMBL3885594 (PROTEIN-PROTEIN INTERACTION)

Molecules with ChEMBL bioactivity

1 molecules (phase ≥1), by development phase (incl. off-target/promiscuous compounds). Patent mentions across the top 20 by phase: 1,538 (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
CHEMBL1232461	MOLIBRESIB	2	1,538

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
7.27	Kd	53.44	nM	CHEMBL5653589
7.27	ED50	53.44	nM	CHEMBL5653589
5.43	Kd	3711	nM	CHEMBL3752910
5.43	ED50	3711	nM	CHEMBL3752910
5.26	IC50	5540	nM	MOLIBRESIB

PubChem BioAssay actives

3 with measured affinity, of 11 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	2148629: Binding affinity to human KPNB1 incubated for 45 mins by Kinobead based pull down assay	kd	0.0534	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2148629: Binding affinity to human KPNB1 incubated for 45 mins by Kinobead based pull down assay	kd	3.7109	uM
2-[(4S)-6-(4-chlorophenyl)-8-methoxy-1-methyl-4H-[1,2,4]triazolo[4,3-a][1,4]benzodiazepin-4-yl]-N-ethylacetamide	2178524: Inhibition of KPNB1 (unknown origin) incubated for 1 hr by colloidal coomassie staining based LC-MS/MS analysis	ic50	5.5400	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	decreases expression	4
bisphenol A	affects expression, decreases expression	3
trichostatin A	decreases expression	2
Air Pollutants	affects cotreatment, increases abundance, increases oxidation, decreases expression	2
Calcitriol	affects expression, decreases expression	2
Tobacco Smoke Pollution	increases expression, affects expression	2
Particulate Matter	decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
beauvericin	affects cotreatment, decreases expression	1
testosterone enanthate	affects expression	1
triphenyl phosphate	affects expression	1
alpha-pinene	affects cotreatment, increases oxidation, increases abundance	1
pirinixic acid	affects binding, decreases expression, increases activity	1
pyrogallol 1,3-dimethyl ether	affects cotreatment, affects localization, decreases expression	1
afimoxifene	decreases expression	1
butyraldehyde	decreases expression	1
methacrylaldehyde	affects cotreatment, increases oxidation, increases abundance	1
epigallocatechin gallate	increases expression	1
di-n-butylphosphoric acid	affects expression	1
enniatins	affects cotreatment, decreases expression	1
belinostat	decreases expression	1
bisphenol B	increases expression	1
bisphenol AF	increases expression	1
Resveratrol	affects cotreatment, increases expression	1
Fulvestrant	decreases expression	1
Acetaminophen	decreases expression	1
Acrolein	affects cotreatment, increases oxidation, increases abundance	1
Vehicle Emissions	increases abundance, increases expression	1
Benzo(a)pyrene	increases methylation	1
Caffeine	decreases phosphorylation	1

ChEMBL screening assays

10 unique, capped per target: 8 binding, 2 functional

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118954	Binding	Binding affinity to KPNB1 in human NCI-H358 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem
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.