TANK

Summary

TANK (TRAF family member associated NFKB activator, HGNC:11562) is a protein-coding gene on chromosome 2q24.2, encoding TRAF family member-associated NF-kappa-B activator (Q92844). Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity.

The TRAF (tumor necrosis factor receptor-associated factor) family of proteins associate with and transduce signals from members of the tumor necrosis factor receptor superfamily. The protein encoded by this gene is found in the cytoplasm and can bind to TRAF1, TRAF2, or TRAF3, thereby inhibiting TRAF function by sequestering the TRAFs in a latent state in the cytoplasm. For example, the protein encoded by this gene can block TRAF2 binding to LMP1, the Epstein-Barr virus transforming protein, and inhibit LMP1-mediated NF-kappa-B activation. Three alternatively spliced transcript variants encoding different isoforms have been found for this gene.

Source: NCBI Gene 10010 — RefSeq curated summary.

At a glance

• GWAS associations: 23
• Clinical variants (ClinVar): 103 total
• Druggable target: yes
• MANE Select transcript: NM_001199135

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:11562
Approved symbol	TANK
Name	TRAF family member associated NFKB activator
Location	2q24.2
Locus type	gene with protein product
Status	Approved
Aliases	I-TRAF
Ensembl gene	ENSG00000136560
Ensembl biotype	protein_coding
OMIM	603893
Entrez	10010

Gene structure

Transcript identifiers

Ensembl transcripts: 71 — 60 protein_coding, 5 protein_coding_CDS_not_defined, 3 nonsense_mediated_decay, 3 retained_intron

ENST00000259075, ENST00000392749, ENST00000402568, ENST00000403609, ENST00000405852, ENST00000406287, ENST00000429217, ENST00000432002, ENST00000432692, ENST00000437623, ENST00000439442, ENST00000440506, ENST00000441987, ENST00000456358, ENST00000457887, ENST00000461338, ENST00000463502, ENST00000468831, ENST00000470324, ENST00000477952, ENST00000483622, ENST00000489393, ENST00000494976, ENST00000882698, ENST00000882699, ENST00000882700, ENST00000882701, ENST00000882702, ENST00000882703, ENST00000882704, ENST00000882705, ENST00000882706, ENST00000882707, ENST00000882708, ENST00000882709, ENST00000882710, ENST00000882711, ENST00000882712, ENST00000882713, ENST00000882714, ENST00000882715, ENST00000882716, ENST00000882717, ENST00000882718, ENST00000882719, ENST00000882720, ENST00000882721, ENST00000882722, ENST00000882723, ENST00000882724, ENST00000882725, ENST00000882726, ENST00000882727, ENST00000882728, ENST00000882729, ENST00000882730, ENST00000882731, ENST00000882732, ENST00000933468, ENST00000966218, ENST00000966219, ENST00000966220, ENST00000966221, ENST00000966222, ENST00000966223, ENST00000966224, ENST00000966225, ENST00000966226, ENST00000966227, ENST00000966228, ENST00000966229

RefSeq mRNA: 3 — MANE Select: NM_001199135 NM_001199135, NM_004180, NM_133484

CCDS: CCDS2215, CCDS46436

Canonical transcript exons

ENST00000392749 — 8 exons

Exon	Start	End
ENSE00000924695	161230971	161231551
ENSE00001676967	161160428	161160486
ENSE00001896167	161235342	161236230
ENSE00003492019	161203487	161203595
ENSE00003508590	161204675	161204793
ENSE00003538914	161179614	161179761
ENSE00003547632	161224631	161224746
ENSE00003600127	161223915	161223991

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 98.04.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 71.2583 / max 2066.1294, expressed in 1821 samples.

FANTOM5 promoters (9 alternative TSS)

Promoter ID	TPM avg	Samples expressed
23302	38.1066	1813
23297	15.0272	713
23301	9.0265	1704
23296	7.2896	826
23300	0.7949	478
23303	0.7650	272
23308	0.1635	53
23295	0.0632	28
23298	0.0217	15

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
monocyte	CL:0000576	98.04	gold quality
mononuclear cell	CL:0000842	97.81	gold quality
calcaneal tendon	UBERON:0003701	97.69	gold quality
leukocyte	CL:0000738	97.63	gold quality
germinal epithelium of ovary	UBERON:0001304	96.87	gold quality
epithelium of nasopharynx	UBERON:0001951	96.69	gold quality
nasopharynx	UBERON:0001728	96.68	gold quality
bone marrow cell	CL:0002092	96.60	gold quality
bone marrow	UBERON:0002371	96.34	gold quality
mammary duct	UBERON:0001765	96.33	gold quality
gall bladder	UBERON:0002110	96.13	gold quality
trabecular bone tissue	UBERON:0002483	95.85	gold quality
lymph node	UBERON:0000029	95.57	gold quality
lower lobe of lung	UBERON:0008949	95.52	gold quality
right lung	UBERON:0002167	95.44	gold quality
epithelium of mammary gland	UBERON:0003244	95.41	gold quality
pericardium	UBERON:0002407	95.38	gold quality
thoracic mammary gland	UBERON:0005200	95.33	gold quality
mammary gland	UBERON:0001911	95.31	gold quality
rectum	UBERON:0001052	95.27	gold quality
mucosa of paranasal sinus	UBERON:0005030	95.23	gold quality
peritoneum	UBERON:0002358	95.13	gold quality
omental fat pad	UBERON:0010414	95.13	gold quality
superficial temporal artery	UBERON:0001614	95.00	gold quality
ganglionic eminence	UBERON:0004023	95.00	gold quality
skeletal muscle tissue of rectus abdominis	UBERON:0004511	94.96	gold quality
islet of Langerhans	UBERON:0000006	94.92	gold quality
right uterine tube	UBERON:0001302	94.92	gold quality
blood	UBERON:0000178	94.89	gold quality
adipose tissue of abdominal region	UBERON:0007808	94.88	gold quality

Single-cell (SCXA)

Detected in 2 experiment(s), a significant marker in 2.

Experiment	Marker?	Max mean expression
E-CURD-46	yes	25.21
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): IRF3, NFKB1, NFKB, NFKBIA, RELA, SOX11

miRNA regulators (miRDB)

10 targeting TANK, 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-3662	99.99	73.82	5684
HSA-MIR-4659A-3P	99.80	72.62	4248
HSA-MIR-4659B-3P	99.80	72.62	4248
HSA-MIR-8076	99.78	68.52	1170
HSA-MIR-4530	99.69	66.47	1509
HSA-MIR-3182	99.40	68.15	2454
HSA-MIR-5584-3P	99.23	68.79	1351
HSA-MIR-449B-3P	99.20	67.24	1047
HSA-MIR-3168	99.08	67.75	1384
HSA-MIR-22-5P	97.67	68.92	1355

Literature-anchored findings (GeneRIF, showing 24)

• association with I kappa B kinase (IKK) regulator NEMO connects IKK complexes with IKK epsilon and TBK1 kinases (PMID:12133833)
• codominant effect of the relevant haplotype of I-TRAF gene in determination of radial bone mineral density (PMID:14499357)
• LTbetaR, CD40 and TANK interact with TRAF3 at sites that promote molecular interactions driving specific signaling (PMID:14517219)
• the scaffold protein TANK is required for the cellular response to TNFalpha by connecting upstream signalling molecules to the IKKs and p65 (PMID:16336209)
• TANK may be a critical adaptor that regulates the assembly of the TANK-binding kinase 1-inducible IkappaB kinase complex with upstream signaling molecules in multiple antiviral pathways (PMID:17327220)
• results suggest that efficient signal transduction upon viral infection requires SINTBAD, TANK and NAP1 because they link TBK1 and IKKi to virus-activated signalling cascades (PMID:17568778)
• Lipopolysaccharide-mediated interferon regulatory factor activation involves TBK1-IKKepsilon-dependent Lys(63)-linked polyubiquitination and phosphorylation of TANK/I-TRAF. (PMID:17823124)
• These findings reveal that the scaffold protein TANK recruits PLK1 to negatively regulate NF-kappaB activation and provide direct evidence that PLK1 is required for the repression function of TANK. (PMID:20484576)
• Expression of TRF2 and TANK1 increased in monoclonal gammopathy of undetermined significance and multiple myeloma. (PMID:20644899)
• SUMO modification of TANK alleviates its repression of TLR7 signalling (PMID:21212807)
• MARCH5 is an authentic E3 ubiquitin ligase and catalyzes K63-linked polyubiquitination of TANK. MARCH5 modulates TLR7 signaling via releasing the inhibitory action of TANK toward TRAF6. (PMID:21625535)
• TANK plays a role in the pathogenesis of acute-on-chronic hepatitis B liver failure (ACLF-HBV) patients and liver cirrhosis patients. (PMID:22225470)
• Studies show that three proteins expressed in HEK-293T cells (NAP1, TANK and TBKBP1) interact with TBK1. (PMID:23286385)
• two TANK gene polymorphisms (rs1921310, rs3820998) do not play a significant role in pathogenesis of chronic periodontitis or peri-implantitis among the Iranian population (PMID:23428248)
• Two SNPs in TANK (rs17705608 and rs7309) were significantly associated with breast cancer risk in our study sample. (PMID:23634849)
• TANK serves as an important negative regulator of NF-kappaB signaling cascades induced by genotoxic stress and IL-1R/Toll-like receptor stimulation in a manner dependent on MCPIP1/USP10-mediated TRAF6 deubiquitination. (PMID:25861989)
• these results suggest that TANK is a novel target of some viral proteases, indicating that some positive RNA viruses have evolved to utilize their major proteases to regulate NF-kappaB activation. (PMID:26363073)
• Molecular basis for TANK recognition by TRAF1 revealed by the crystal structure of TRAF1/TANK complex has been reported. (PMID:28155233)
• Data suggest that Encephalomyocarditis virus 3C protease cleaves TANK and disrupts the TANK-TBK1-IKKepsilon-IRF3 complex, resulting in reduction in IRF3 phosphorylation and type I interferon production. (TANK = TRAF family member associated NFKB activator; TBK1 = TANK binding kinase 1; IKKepsilon = inhibitor of nuclear factor kappa B kinase subunit epsilon; IRF3 = interferon regulatory factor 3) (PMID:28487378)
• Therefore, Seneca Valley virus suppressed antiviral interferon production to escape host antiviral innate immune responses by cleaving host adaptor molecules MAVS, TRIF, and TANK by its 3C protease. (PMID:28566380)
• SNP rs197273 in TANK is associated both with gene expression and regional methylation. Neuroimaging studies among up to 1896 adolescents reveal that TANK is involved in the control of brain activity in areas of aversive interoceptive processing, including the insular cortex. TANK is associated with enhanced aversive emotional processing that better protects from the establishment of alcohol drinking behavior. (PMID:30721969)
• CARD14/CARMA2sh and TANK differentially regulate poly(I:C)-induced inflammatory reaction in keratinocytes. (PMID:31486084)
• UBAC1/KPC2 Regulates TLR3 Signaling in Human Keratinocytes through Functional Interaction with the CARD14/CARMA2sh-TANK Complex. (PMID:33316896)
• TANK shapes an immunosuppressive microenvironment and predicts prognosis and therapeutic response in glioma. (PMID:37215097)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tank	ENSDARG00000067723
mus_musculus	Tank	ENSMUSG00000064289
rattus_norvegicus	Tank	ENSRNOG00000008859

Protein

Protein identifiers

TRAF family member-associated NF-kappa-B activator — Q92844 (reviewed: Q92844)

Alternative names: TRAF-interacting protein

All UniProt accessions (13): Q92844, E7EM55, E7EMT6, E7ENY2, E7EQA9, E7ERM9, E7EV32, E7EVA2, E7EW82, E7EWR8, E9PEK1, H7BZ28, H7C3L4

UniProt curated annotations — full annotation on UniProt →

Function. Adapter protein involved in I-kappa-B-kinase (IKK) regulation which constitutively binds TBK1 and IKBKE playing a role in antiviral innate immunity. Acts as a regulator of TRAF function by maintaining them in a latent state. Blocks TRAF2 binding to LMP1 and inhibits LMP1-mediated NF-kappa-B activation. Negatively regulates NF-kappaB signaling and cell survival upon DNA damage. Plays a role as an adapter to assemble ZC3H12A, USP10 in a deubiquitination complex which plays a negative feedback response to attenuate NF-kappaB activation through the deubiquitination of IKBKG or TRAF6 in response to interleukin-1-beta (IL1B) stimulation or upon DNA damage. Promotes UBP10-induced deubiquitination of TRAF6 in response to DNA damage. May control negatively TRAF2-mediated NF-kappa-B activation signaled by CD40, TNFR1 and TNFR2.

Subunit / interactions. Homodimer. Found in a deubiquitination complex with TANK, USP10 and ZC3H12A; this complex inhibits genotoxic stress- or interleukin-1-beta-mediated NF-kappaB activation by promoting IKBKG or TRAF6 deubiquitination. Interacts with IKBKG; this interaction increases in response to DNA damage. Interacts with TRAF6; this interaction increases in response to DNA damage and recruits USP10 to the ubiquitinated TRAF6. Interacts with USP10; this interaction increases in response to DNA damage. Interacts with ZC3H12A; this interaction increases in response to DNA damage. Interacts with TBK1. Interacts with IKBKE. Also interacts with TRAF1, TRAF2, and TRAF3 by binding to their TRAF-C domains; the interaction with TRAF2 is disrupted by the phosphorylation of TANK by IKBKE. Interacts more strongly with TRAF1 and TRAF2 than TRAF3. Interacts with IKBKG; the interaction is enhanced by IKBKE and TBK1. Part of a ternary complex consisting of TANK, IKBKB and IKBKG. (Microbial infection) Interacts with vaccinia virus protein C6. (Microbial infection) Interacts with Seneca Valley virus protease 3C; this interaction allows the cleavage of TANK and subsequent suppression of host innate immunity.

Subcellular location. Cytoplasm.

Tissue specificity. Ubiquitous.

Post-translational modifications. Phosphorylated by IKBKE. (Microbial infection) Cleaved by encephalomyocarditis virus (EMCV) protease 3C. This cleavage allows the virus to disrupt the TANK-TBK1-IKKepsilon-IRF3 complex, thereby inhibiting the induction of the IFN-beta signal pathway. (Microbial infection) Cleaved by Seneca Valley virus protease 3C allowing the virus to suppress interferon type-I through both RIG-I and Toll-like receptor-dependent pathways.

Isoforms (3)

UniProt ID	Names	Canonical?
Q92844-1	Long	yes
Q92844-2	Short
Q92844-3	3

RefSeq proteins (3): NP_001186064, NP_004171, NP_597841 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR024581	TBD	Domain
IPR039669	TANK	Family
IPR041641	CALCOCO1/2_Zn_UBZ1	Domain

Pfam: PF12845

UniProt features (54 total): mutagenesis site 13, modified residue 11, sequence conflict 7, binding site 4, site 4, region of interest 4, splice variant 4, sequence variant 3, chain 1, zinc finger region 1, strand 1, coiled-coil region 1

Structure

Experimental structures (PDB)

3 structures.

PDB	Method	Resolution (Å)
1L0A	X-RAY DIFFRACTION	2.9
5H10	X-RAY DIFFRACTION	3.21
1KZZ	X-RAY DIFFRACTION	3.5

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q92844-F1	60.31	0.22

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 (4): 197 (cleavage by emcv protease 3c); 272–273 ((microbial infection) cleavage; by viral seneca valley virus protease 3c); 291–292 ((microbial infection) cleavage; by viral seneca valley virus protease 3c); 291 (cleavage by emcv protease 3c)

Ligand- & substrate-binding residues (4): 420; 396; 399; 416

Post-translational modifications (11): 1, 126, 129, 178, 208, 213, 225, 228, 341, 354, 357

Mutagenesis-validated functional residues (13):

Position	Phenotype
182	abolishes interaction with traf2 and traf3.
184	abolishes interaction with traf2 and traf3.
185	abolishes interaction with traf2; greatly diminishes interaction with traf3.
188	diminishes interaction with traf2 and traf3.
194	diminishes interaction with traf2 and traf3.
197	no effect on cleavage by seneca valley virus protease 3c.
247	no effect on cleavage by seneca valley virus protease 3c.
251	no effect on cleavage by seneca valley virus protease 3c.
262	no effect on cleavage by seneca valley virus protease 3c.
266	no effect on cleavage by seneca valley virus protease 3c.
267	no effect on cleavage by seneca valley virus protease 3c.
272	complete loss of cleavage by seneca valley virus protease 3c.
291	complete loss of cleavage by seneca valley virus protease 3c.

Function

Pathways and Gene Ontology

Reactome pathways

13 pathways

ID	Pathway
R-HSA-9013973	TICAM1-dependent activation of IRF3/IRF7
R-HSA-933541	TRAF6 mediated IRF7 activation
R-HSA-936964	Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)
R-HSA-9824878	Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7
R-HSA-9828211	Regulation of TBK1, IKKε-mediated activation of IRF3, IRF7 upon TLR3 ligation
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168249	Innate Immune System
R-HSA-168256	Immune System
R-HSA-168898	Toll-like Receptor Cascades
R-HSA-168928	DDX58/IFIH1-mediated induction of interferon-alpha/beta
R-HSA-937061	TRIF (TICAM1)-mediated TLR4 signaling

MSigDB gene sets: 700 (showing top): REACTOME_DDX58_IFIH1_MEDIATED_INDUCTION_OF_INTERFERON_ALPHA_BETA, BIOCARTA_TNFR2_PATHWAY, GOBP_RESPONSE_TO_NITROGEN_COMPOUND, RODRIGUES_THYROID_CARCINOMA_ANAPLASTIC_UP, GOBP_RESPONSE_TO_IONIZING_RADIATION, MULLIGHAN_NPM1_SIGNATURE_3_UP, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_POSITIVE_REGULATION_OF_ADAPTIVE_IMMUNE_RESPONSE, KEGG_ADIPOCYTOKINE_SIGNALING_PATHWAY, RODRIGUES_THYROID_CARCINOMA_POORLY_DIFFERENTIATED_UP, GOBP_REGULATION_OF_PHOSPHORYLATION, SWEET_KRAS_ONCOGENIC_SIGNATURE, GOBP_POSITIVE_REGULATION_OF_TYPE_I_INTERFERON_PRODUCTION, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_REGULATION_OF_MRNA_CATABOLIC_PROCESS

GO Biological Process (14): DNA damage response (GO:0006974), signal transduction (GO:0007165), canonical NF-kappaB signal transduction (GO:0007249), negative regulation of tumor necrosis factor-mediated signaling pathway (GO:0010804), positive regulation of type I interferon production (GO:0032481), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), defense response to virus (GO:0051607), type I interferon-mediated signaling pathway (GO:0060337), cellular response to interleukin-1 (GO:0071347), cellular response to tumor necrosis factor (GO:0071356), cellular response to ionizing radiation (GO:0071479), positive regulation of protein deubiquitination (GO:1903003), positive regulation of ubiquitin-specific protease activity (GO:2000158)

GO Molecular Function (8): zinc ion binding (GO:0008270), ubiquitin protein ligase binding (GO:0031625), deubiquitinase activator activity (GO:0035800), molecular adaptor activity (GO:0060090), molecular function inhibitor activity (GO:0140678), cysteine-type deubiquitinase activity (GO:0004843), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (4): cytoplasm (GO:0005737), cytosol (GO:0005829), protein-containing complex (GO:0032991), serine/threonine protein kinase complex (GO:1902554)

Reactome top-level categories

Rollup of top-10 pathways:

Category	Pathways
Toll-like Receptor Cascades	2
Innate Immune System	2
Toll Like Receptor 3 (TLR3) Cascade	1
DDX58/IFIH1-mediated induction of interferon-alpha/beta	1
TRIF (TICAM1)-mediated TLR4 signaling	1
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	1
TICAM1-dependent activation of IRF3/IRF7	1
Toll Like Receptor 4 (TLR4) Cascade	1
Immune System	1
MyD88-independent TLR4 cascade	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
cellular response to cytokine stimulus	2
deubiquitinase activity	2
binding	2
cellular anatomical structure	2
cellular response to stress	1
cell communication	1
cellular process	1
signaling	1
regulation of cellular process	1
cellular response to stimulus	1
intracellular signaling cassette	1
negative regulation of cytokine-mediated signaling pathway	1
regulation of tumor necrosis factor-mediated signaling pathway	1
tumor necrosis factor-mediated signaling pathway	1
positive regulation of cytokine production	1
regulation of type I interferon production	1
type I interferon production	1
positive regulation of intracellular signal transduction	1
negative regulation of intracellular signal transduction	1
defense response	1
response to virus	1
cellular response to type I interferon	1
interferon-mediated signaling pathway	1
response to interleukin-1	1
response to tumor necrosis factor	1
response to ionizing radiation	1
cellular response to radiation	1
protein deubiquitination	1
regulation of protein deubiquitination	1
positive regulation of protein modification by small protein conjugation or removal	1
cysteine-type deubiquitinase activity	1
positive regulation of peptidase activity	1
transition metal ion binding	1
ubiquitin-like protein ligase binding	1
peptidase activator activity	1
molecular_function	1
molecular function regulator activity	1
cysteine-type peptidase activity	1

Protein interactions and networks

STRING

1801 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TANK	TRAF3	Q13114	998
TANK	IKBKE	Q14164	998
TANK	TBK1	Q9UHD2	998
TANK	TRADD	Q15628	990
TANK	IKBKG	Q9Y6K9	990
TANK	TBKBP1	A7MCY6	985
TANK	TRAF6	Q9Y4K3	962
TANK	MAVS	Q7Z434	950
TANK	ZC3H12A	Q5D1E8	889
TANK	AZI2	Q9H6S1	884
TANK	TRAF1	Q13077	875
TANK	FADD	Q13158	872
TANK	IRF3	Q14653	868
TANK	RIPK1	Q13546	825
TANK	BIRC2	Q13490	818

IntAct

147 interactions, top by confidence:

A	B	Type	Score
IKBKG	IKBKB	psi-mi:“MI:0914”(association)	0.980
SUMO1	UBE2I	psi-mi:“MI:0914”(association)	0.950
TANK	TBK1	psi-mi:“MI:0915”(physical association)	0.930
TBK1	TANK	psi-mi:“MI:0915”(physical association)	0.930
TRAF3	TANK	psi-mi:“MI:0407”(direct interaction)	0.870
TRAF3	TANK	psi-mi:“MI:0915”(physical association)	0.870
TBK1	TBKBP1	psi-mi:“MI:0914”(association)	0.860
TRAF2	TANK	psi-mi:“MI:0915”(physical association)	0.850
TANK	IKBKE	psi-mi:“MI:0915”(physical association)	0.830
TANK	IKBKE	psi-mi:“MI:0195”(covalent binding)	0.830
IKBKE	TANK	psi-mi:“MI:0915”(physical association)	0.830
RARA	NCOR1	psi-mi:“MI:0914”(association)	0.800
TRAF2	HTRA2	psi-mi:“MI:0914”(association)	0.750
TANK	IKBKG	psi-mi:“MI:0915”(physical association)	0.740
CFTR	ESYT2	psi-mi:“MI:2364”(proximity)	0.710
PLK1	TANK	psi-mi:“MI:0915”(physical association)	0.670
TANK	PLK1	psi-mi:“MI:0915”(physical association)	0.670
SEPTIN2	SEPTIN8	psi-mi:“MI:0914”(association)	0.670
TANK	CEP63	psi-mi:“MI:0915”(physical association)	0.660

BioGRID (326): TANK (Two-hybrid), TANK (Two-hybrid), CEP63 (Two-hybrid), TANK (Affinity Capture-RNA), TBK1 (Affinity Capture-Western), TANK (Affinity Capture-Western), TANK (Affinity Capture-MS), TANK (Affinity Capture-MS), ZC3H12A (Two-hybrid), TANK (Proximity Label-MS), TANK (Proximity Label-MS), TANK (Affinity Capture-MS), IKBKG (Affinity Capture-Western), ZC3H12A (Affinity Capture-Western), ZC3H12A (Reconstituted Complex)

ESM2 similar proteins: A0A087WRU1, A0JNH1, A2RUB1, A6QNQ6, B0S6S9, B1WC58, D3Z987, D3ZJ47, E1BC15, O60673, P28358, P28359, P56716, P70347, Q0P5X5, Q0VAV2, Q0VBV7, Q15468, Q2M2Z5, Q3UXL4, Q3V089, Q49A88, Q569L8, Q5BQN8, Q5CZC0, Q5QGS0, Q5T1N1, Q5VWN6, Q60988, Q61493, Q62924, Q6ZP01, Q6ZU52, Q6ZVD7, Q80U59, Q80WQ8, Q86WS4, Q86YC2, Q8CB14, Q8IUR6

Diamond homologs: P70347, Q92844

SIGNOR signaling

11 interactions.

A	Effect	B	Mechanism
TANK	“up-regulates activity”	DUSP14	ubiquitination
IKBKE	“down-regulates activity”	TANK	phosphorylation
TANK	“down-regulates activity”	TRAF2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 102 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
Regulation of TBK1, IKKε (IKBKE)-mediated activation of IRF3, IRF7	5	47.6×	4e-06
TICAM1, RIP1-mediated IKK complex recruitment	5	37.6×	1e-05
Activation of IRF3, IRF7 mediated by TBK1, IKKε (IKBKE)	5	37.6×	1e-05
TNFR1-induced proapoptotic signaling	6	32.9×	3e-06
TNF signaling	6	31.7×	3e-06
IKK complex recruitment mediated by RIP1	5	31.0×	3e-05
TNFR1-induced NF-kappa-B signaling pathway	7	29.4×	1e-06
Cytosolic tRNA aminoacylation	5	27.4×	6e-05

GO biological processes:

GO term	Partners	Fold	FDR
positive regulation of type I interferon production	7	31.7×	7e-07
tumor necrosis factor-mediated signaling pathway	8	28.4×	2e-07
canonical NF-kappaB signal transduction	7	27.6×	2e-06
mRNA stabilization	5	19.7×	7e-04
type I interferon-mediated signaling pathway	5	18.5×	7e-04
cellular response to retinoic acid	6	15.1×	5e-04
positive regulation of protein ubiquitination	6	13.8×	7e-04
obsolete positive regulation of NF-kappaB transcription factor activity	6	13.3×	7e-04

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	0
Likely pathogenic	0
Uncertain significance	75
Likely benign	4
Benign	4

Top pathogenic / likely-pathogenic (0)

SpliceAI

4393 predictions. Top by Δscore:

Variant	Effect	Δscore
2:161179610:GCAGA:G	acceptor_loss	1.0000
2:161179611:CA:C	acceptor_loss	1.0000
2:161179612:A:AG	acceptor_gain	1.0000
2:161179613:G:GA	acceptor_gain	1.0000
2:161179613:GA:G	acceptor_gain	1.0000
2:161179613:GAC:G	acceptor_gain	1.0000
2:161179613:GACC:G	acceptor_gain	1.0000
2:161179613:GACCT:G	acceptor_gain	1.0000
2:161179757:AAAAG:A	donor_loss	1.0000
2:161179760:AGGTG:A	donor_loss	1.0000
2:161179761:GG:G	donor_loss	1.0000
2:161179762:G:A	donor_loss	1.0000
2:161203485:A:AG	acceptor_gain	1.0000
2:161203486:G:GG	acceptor_gain	1.0000
2:161203593:AAG:A	donor_loss	1.0000
2:161203594:AGGTA:A	donor_loss	1.0000
2:161203596:G:A	donor_loss	1.0000
2:161203597:T:A	donor_loss	1.0000
2:161224628:TAGG:T	acceptor_loss	1.0000
2:161224629:A:AG	acceptor_gain	1.0000
2:161224629:A:G	acceptor_loss	1.0000
2:161224629:AG:A	acceptor_gain	1.0000
2:161224629:AGG:A	acceptor_gain	1.0000
2:161224629:AGGG:A	acceptor_gain	1.0000
2:161224630:G:A	acceptor_gain	1.0000
2:161224630:G:GA	acceptor_gain	1.0000
2:161224630:GGG:G	acceptor_gain	1.0000
2:161224630:GGGG:G	acceptor_gain	1.0000
2:161224630:GGGGT:G	acceptor_gain	1.0000
2:161224743:ACTG:A	donor_gain	1.0000

AlphaMissense

2813 scored. Top likely-pathogenic:

Variant	Protein change	am_pathogenicity
2:161179712:G:C	R17P	0.997
2:161179688:T:C	L9P	0.996
2:161224660:T:C	L145P	0.994
2:161179688:T:A	L9H	0.992
2:161179705:G:C	A15P	0.992
2:161235432:T:C	F398L	0.992
2:161235434:C:A	F398L	0.992
2:161235434:C:G	F398L	0.992
2:161235490:T:C	L417P	0.992
2:161179696:G:C	A12P	0.991
2:161179717:G:C	A19P	0.991
2:161179738:G:C	A26P	0.991
2:161203560:T:C	L58P	0.991
2:161235426:T:C	C396R	0.991
2:161179699:T:G	Y13D	0.989
2:161179708:T:C	F16L	0.989
2:161179710:C:A	F16L	0.989
2:161179710:C:G	F16L	0.989
2:161235435:T:C	C399R	0.989
2:161235437:T:G	C399W	0.987
2:161235427:G:A	C396Y	0.986
2:161179697:C:A	A12E	0.985
2:161179711:C:G	R17G	0.985
2:161235436:G:A	C399Y	0.985
2:161203518:A:C	Q44P	0.984
2:161235428:T:G	C396W	0.984
2:161235435:T:A	C399S	0.984
2:161235436:G:C	C399S	0.984
2:161235488:T:A	H416Q	0.984
2:161235488:T:G	H416Q	0.984

dbSNP variants (sampled 300 via entrez): RS1000000781 (2:161154844 A>G), RS1000017619 (2:161177462 A>G), RS1000024096 (2:161175221 A>G), RS1000049075 (2:161160859 C>A,G), RS1000096892 (2:161167135 A>G), RS1000116131 (2:161236099 T>A), RS1000144752 (2:161199007 A>C,G), RS1000172595 (2:161228194 T>C), RS1000188126 (2:161142088 A>G), RS1000188532 (2:161236387 G>T), RS1000225527 (2:161214467 C>T), RS1000240609 (2:161141682 A>C,G), RS1000281844 (2:161220525 C>T), RS1000320229 (2:161161862 G>A), RS1000399034 (2:161160626 A>G)

Disease associations

OMIM: gene MIM:603893 | disease phenotypes:

GenCC curated gene-disease

Mondo (0):

Orphanet (0):

HPO phenotypes

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

GWAS associations

23 associations (top):

Study	Trait	p-value
GCST001402_2	Treatment response for severe sepsis	6.000000e-06
GCST001521_25	Subcutaneous adipose tissue	6.000000e-07
GCST001762_411	Obesity-related traits	2.000000e-06
GCST001844_1	Dietary macronutrient intake	1.000000e-07
GCST001872_8	Presence of antiphospholipid antibodies	3.000000e-06
GCST002363_13	Response to anti-retroviral therapy (ddI/d4T) in HIV-1 infection (Grade 3 peripheral neuropathy)	2.000000e-08
GCST002598_20	Educational attainment	2.000000e-07
GCST004026_2	Alcohol consumption	7.000000e-08
GCST006269_719	General cognitive ability	2.000000e-09
GCST007044_8	Extremely high intelligence	3.000000e-08
GCST007277_3	Tourette syndrome	2.000000e-07
GCST007327_103	Smoking status (ever vs never smokers)	4.000000e-10
GCST007576_228	Chronotype	3.000000e-08
GCST008396_2	Educational attainment (years of education)	4.000000e-08
GCST009505_1	Weight	3.000000e-07
GCST009524_317	Household income (MTAG)	3.000000e-09
GCST010698_7	Subcortical volume (min-P)	5.000000e-08
GCST010699_92	Brain morphology (min-P)	7.000000e-13
GCST010700_32	Cortical thickness (MOSTest)	1.000000e-08
GCST010701_4	Cortical surface area (MOSTest)	1.000000e-08
GCST010702_173	Subcortical volume (MOSTest)	5.000000e-16
GCST010703_19	Brain morphology (MOSTest)	1.000000e-09
GCST90002401_200	Platelet distribution width	7.000000e-11

EFO canonical traits (12, from GWAS)

EFO ID	Trait name
EFO:0003940	physical activity
EFO:0003939	energy intake
EFO:0000180	HIV-1 infection
EFO:0004784	self reported educational attainment
EFO:0004337	intelligence
EFO:0004318	smoking behavior
EFO:0008328	chronotype measurement
EFO:0004338	body weight
EFO:0009695	household income
EFO:0004346	neuroimaging measurement
EFO:0004840	cortical thickness
EFO:0007984	platelet component distribution width

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4523420 (SINGLE PROTEIN)

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

PharmGKB variants

1 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs1267067	TANK		0.00	0

ChEMBL bioactivities

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

pChembl	Type	Value	Unit	Molecule
7.49	Kd	32.29	nM	CHEMBL5653589
7.29	ED50	50.76	nM	CHEMBL5653589
5.80	Kd	1567	nM	CHEMBL4462318
5.47	Kd	3418	nM	CHEMBL4443828
5.07	Kd	8501	nM	CHEMBL3752910

PubChem BioAssay actives

4 with measured affinity, of 6 total; 4 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	2149540: Binding affinity to human TANK incubated for 45 mins by Kinobead based pull down assay	kd	0.0323	uM
2,6-difluoro-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]benzenesulfonamide	1573308: Binding affinity to TANK in SILAC-labeled human MDA-MB-231 cells lysate by mass spectrometry based kinAffinity assay	kd	1.5670	uM
2,5-difluoro-N-[3-fluoro-4-[6-methoxy-7-[3-(4-methylpiperazin-1-yl)propoxy]quinolin-4-yl]oxyphenyl]benzenesulfonamide	1573308: Binding affinity to TANK in SILAC-labeled human MDA-MB-231 cells lysate by mass spectrometry based kinAffinity assay	kd	3.4180	uM
4-methyl-3-[(1-methyl-6-pyridin-3-ylpyrazolo[3,4-d]pyrimidin-4-yl)amino]-N-[3-(trifluoromethyl)phenyl]benzamide	2149540: Binding affinity to human TANK incubated for 45 mins by Kinobead based pull down assay	kd	8.5012	uM

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
bisphenol A	affects expression, affects methylation	2
sodium arsenite	increases expression	2
Estradiol	affects reaction, increases expression, affects expression, affects binding	2
Valproic Acid	decreases methylation, increases expression	2
Magnetite Nanoparticles	affects cotreatment, increases expression	2
FR900359	decreases phosphorylation	1
dicrotophos	decreases expression	1
bufotalin	increases expression	1
triphenyl phosphate	affects expression	1
diepoxybutane	increases expression	1
beta-lapachone	increases expression	1
4-hydroxy-2-nonenal	decreases expression	1
coumarin	decreases phosphorylation	1
epigallocatechin gallate	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
usnic acid	increases expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
ICG 001	increases expression	1
abrine	increases expression	1
ON 01910	increases expression	1
jinfukang	decreases expression	1
Imatinib Mesylate	increases expression	1
Bortezomib	increases expression	1
Acetylcysteine	decreases expression	1
Arsenic	affects cotreatment, decreases expression	1
Caffeine	decreases phosphorylation	1
Carbamazepine	affects expression	1
Cisplatin	increases expression	1
Demecolcine	increases expression	1

ChEMBL screening assays

2 unique, capped per target: 2 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4371438	Binding	Binding affinity to TANK in SILAC-labeled human MDA-MB-231 cells lysate by mass spectrometry based kinAffinity assay	Discovery of N-[4-(Quinolin-4-yloxy)phenyl]benzenesulfonamides as Novel AXL Kinase Inhibitors. — J Med Chem

Cellosaurus cell lines

7 cell lines: 6 cancer cell line, 1 transformed cell line

First 10 cell lines (id-ordered, not curated):

Cellosaurus	Name	Category	Sex
CVCL_B2I4	Abcam HeLa TANK KO	Cancer cell line	Female
CVCL_B3K1	Abcam HEK293T TRAF2 KO	Transformed cell line	Female
CVCL_B8A3	Abcam Raji TRAF2 KO	Cancer cell line	Male
CVCL_C0AX	Abcam THP-1 TRAF2 KO	Cancer cell line	Male
CVCL_C7CK	Abcam PC-3 TRAF2 KO	Cancer cell line	Male
CVCL_TR52	HAP1 TANK (-) 1	Cancer cell line	Male
CVCL_TR53	HAP1 TANK (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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