TAB2

Summary

TAB2 (TGF-beta activated kinase 1 (MAP3K7) binding protein 2, HGNC:17075) is a protein-coding gene on chromosome 6q25.1, encoding TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (Q9NYJ8). Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of ‘Lys-63’-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF).

The protein encoded by this gene is an activator of MAP3K7/TAK1, which is required for for the IL-1 induced activation of nuclear factor kappaB and MAPK8/JNK. This protein forms a kinase complex with TRAF6, MAP3K7 and TAB1, and it thus serves as an adaptor that links MAP3K7 and TRAF6. This protein, along with TAB1 and MAP3K7, also participates in the signal transduction induced by TNFSF11/RANKl through the activation of the receptor activator of NF-kappaB (TNFRSF11A/RANK), which may regulate the development and function of osteoclasts. Studies of the related mouse protein indicate that it functions to protect against liver damage caused by chemical stressors. Mutations in this gene cause congenital heart defects, multiple types, 2 (CHTD2). Alternative splicing results in multiple transcript variants.

Source: NCBI Gene 23118 — RefSeq curated summary.

At a glance

• Gene–disease (curated): congenital heart defects, multiple types, 2 (Definitive, GenCC) — +2 more curated relationships
• GWAS associations: 14
• Clinical variants (ClinVar): 226 total — 23 pathogenic, 9 likely-pathogenic
• Phenotypes (HPO): 13
• Druggable target: yes
• Dosage sensitivity (ClinGen): haploinsufficiency little evidence, triplosensitivity no evidence
• MANE Select transcript: NM_001292034

Identifiers

Gene identifiers

Field	Value
HGNC ID	HGNC:17075
Approved symbol	TAB2
Name	TGF-beta activated kinase 1 (MAP3K7) binding protein 2
Location	6q25.1
Locus type	gene with protein product
Status	Approved
Aliases	KIAA0733
Ensembl gene	ENSG00000055208
Ensembl biotype	protein_coding
OMIM	605101
Entrez	23118

Gene structure

Transcript identifiers

Ensembl transcripts: 17 — 13 protein_coding, 3 protein_coding_CDS_not_defined, 1 nonsense_mediated_decay

ENST00000367456, ENST00000461481, ENST00000470466, ENST00000484505, ENST00000606202, ENST00000606797, ENST00000636456, ENST00000637181, ENST00000703212, ENST00000703213, ENST00000894599, ENST00000894600, ENST00000894601, ENST00000894602, ENST00000919129, ENST00000919130, ENST00000919131

RefSeq mRNA: 4 — MANE Select: NM_001292034 NM_001292034, NM_001292035, NM_001369506, NM_015093

CCDS: CCDS5214

Canonical transcript exons

ENST00000637181 — 7 exons

Exon	Start	End
ENSE00002151893	149378018	149379518
ENSE00002197520	149369909	149370099
ENSE00003473530	149397604	149397764
ENSE00003587091	149397969	149398062
ENSE00003656381	149399104	149399184
ENSE00003793160	149317712	149318015
ENSE00003794431	149409577	149411607

Expression profiles

Bgee: expression breadth ubiquitous, 293 present calls, max score 96.23.

FANTOM5 (CAGE): breadth ubiquitous, TPM avg 21.5861 / max 305.5439, expressed in 1780 samples.

FANTOM5 promoters (12 alternative TSS)

Promoter ID	TPM avg	Samples expressed
70472	9.3251	1704
70471	4.5628	1499
70473	2.8042	1255
70474	1.7455	1070
70469	1.0836	542
70462	1.0777	85
70467	0.4117	79
70470	0.2644	120
70464	0.1190	45
70466	0.0912	49

Top tissues by expression

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

Tissue	Anatomy ID	Expression score	Quality
parotid gland	UBERON:0001831	96.23	gold quality
ventricular zone	UBERON:0003053	95.60	gold quality
colonic epithelium	UBERON:0000397	95.26	gold quality
gastrocnemius	UBERON:0001388	94.95	gold quality
muscle of leg	UBERON:0001383	94.81	gold quality
cartilage tissue	UBERON:0002418	94.78	gold quality
hair follicle	UBERON:0002073	94.69	gold quality
islet of Langerhans	UBERON:0000006	94.68	gold quality
monocyte	CL:0000576	94.54	gold quality
leukocyte	CL:0000738	94.54	gold quality
muscle layer of sigmoid colon	UBERON:0035805	94.53	gold quality
mononuclear cell	CL:0000842	94.50	gold quality
biceps brachii	UBERON:0001507	94.38	gold quality
cranial nerve II	UBERON:0000941	94.21	gold quality
muscle organ	UBERON:0001630	94.18	gold quality
periodontal ligament	UBERON:0008266	94.16	gold quality
skeletal muscle tissue of biceps brachii	UBERON:0004502	94.06	gold quality
choroid plexus epithelium	UBERON:0003911	94.02	gold quality
sigmoid colon	UBERON:0001159	93.80	gold quality
ganglionic eminence	UBERON:0004023	93.71	gold quality
diaphragm	UBERON:0001103	93.61	gold quality
hindlimb stylopod muscle	UBERON:0004252	93.61	gold quality
bone marrow cell	CL:0002092	93.47	gold quality
calcaneal tendon	UBERON:0003701	93.42	gold quality
amniotic fluid	UBERON:0000173	93.34	gold quality
trabecular bone tissue	UBERON:0002483	93.29	gold quality
lower esophagus	UBERON:0013473	93.22	gold quality
lower esophagus muscularis layer	UBERON:0035833	93.21	gold quality
caput epididymis	UBERON:0004358	93.20	gold quality
corpus epididymis	UBERON:0004359	93.18	gold quality

Single-cell (SCXA)

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

Experiment	Marker?	Max mean expression
E-HCAD-35	yes	27.61
E-ANND-3	no	0.00

Regulation

Is transcription factor: no

Upstream regulators (CollecTRI, top): HR, NR2C2

miRNA regulators (miRDB)

223 targeting TAB2, 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-4262	100.00	73.26	3931
HSA-MIR-340-5P	100.00	72.50	4437
HSA-MIR-5692A	100.00	74.40	6850
HSA-MIR-3667-3P	99.99	67.17	1636
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-4500	99.99	72.72	2367
HSA-MIR-520D-5P	99.98	73.34	4883
HSA-MIR-524-5P	99.98	73.43	4882
HSA-MIR-4775	99.98	75.00	6394
HSA-LET-7A-5P	99.98	72.29	1790
HSA-LET-7B-5P	99.98	72.31	1790
HSA-LET-7C-5P	99.98	72.29	1790
HSA-LET-7E-5P	99.98	72.29	1790
HSA-LET-7F-5P	99.98	72.56	1784
HSA-LET-7G-5P	99.98	72.37	1784
HSA-LET-7I-5P	99.98	72.37	1788
HSA-MIR-98-5P	99.98	72.33	1787
HSA-MIR-302C-5P	99.97	72.56	3642
HSA-MIR-6793-5P	99.97	65.95	758
HSA-MIR-3148	99.97	75.06	6478
HSA-MIR-6888-3P	99.97	65.95	1170
HSA-MIR-548AJ-3P	99.96	73.38	5345
HSA-MIR-548X-3P	99.96	73.38	5345
HSA-MIR-493-5P	99.96	72.47	2382
HSA-LET-7D-5P	99.96	71.76	1632
HSA-MIR-4458	99.96	71.64	1650
HSA-MIR-590-3P	99.96	74.34	6478

Functional genomics

ClinGen dosage: haploinsufficiency 1 (little evidence), triplosensitivity 0 (no evidence). ClinGen Gene Dosage Map

Literature-anchored findings (GeneRIF, showing 40)

• Interleukin-1 (IL-1) receptor-associated kinase-dependent IL-1-induced signaling complexes phosphorylate TAK1 and TAB2 at the plasma membrane and activate TAK1 in the cytosol. (PMID:12242293)
• Both TAB2 and SUMO are involved in NF-kappaB activation and may thus be involved in type 1 diabetes through apoptosis in pancreatic beta-cells. (PMID:15220215)
• Data show that TAB2 and TAB3 are receptors that bind preferentially to polyubiquitin chains through a highly conserved zinc finger (ZnF) domain, and activate NF-kappa B and IKK. (PMID:15327770)
• characterized the molecular mechanisms of cellular stress-induced TAK1 activation, focusing mainly on the phosphorylation of TAK1 at Thr-187 and Ser-192 in the activation loop; TAB1 and TAB2 were differentially involved in the phosphorylation of TAK1 (PMID:15590691)
• Involvement of the TAB2/TRAF6/TAK1 signalling complex in the Edar signal transduction pathway has important implications for understanding of NF-kappaB activation and anhidrotic ectodermal dysplasia in human. (PMID:16251197)
• Single nucleotide polymorphism in Graves’ disease in a large UK Caucasian Graves’ disease data set. (PMID:16384851)
• A candidate gene in ectodermal dysplasia. (PMID:16527194)
• MAP3K7IP2 SNP did not significantly influence predisposition to and features of rheumatoid arthritis, in contrast to previous genetic and functional evidence that suggested its involvement. (PMID:16755651)
• The TAB2/TAB3 interaction with TAK1 is crucial for the activation of signaling cascades mediated by interleukin-1, tumor necrosis factor, and receptor activator of nuclear factor-kappa B ligand (RANKL). (PMID:17158449)
• The current data support the notion that LMP1 modifies stress-induced apoptosis in epithelial cells through molecular interactions downstream of its C-terminal signaling domain. (PMID:17586463)
• Tax induced persistent overexpression of TAK1-binding protein 2 (TAB2), but not TAB3, which is essential for TAK1 activation. (PMID:17626013)
• TAB2 may be critically involved in Tax-mediated activation of TAK1 and that NF-kappaB-activating TRAF family proteins are potential cellular E3 ubiquitin ligases toward Tax. (PMID:17986383)
• Here the authors analyze crystal structures of the TAB2 NZF domain bound to Lys63-linked di- and triubiquitin, revealing that TAB2 binds adjacent ubiquitin moieties via two distinct binding sites. (PMID:19935683)
• To confirm the role of this gene in CHDs, we performed mutation analysis of TAB2 in patients with a CHD, which revealed two d missense mutations. (PMID:20493459)
• Co-expression of RelA and/or TAB2 markedly increased Tax-mediated NF-kappaB activation. (PMID:20875659)
• microRNA-155 negatively regulates the expression of TAB2 and downstream IFN-gamma-inducible protein of 10 kDa as a negative feedback system. (PMID:20948191)
• The ability of human Trim5alpha to regulate TAB2 levels, to activate NF-kappaB, and to recognize retroviral capsids are genetically separable. (PMID:21035162)
• these studies show that the TAK1-TAB2-TAB3 signaling axis is critical for carcinoma-induced bone lesions, mediating expression of proinvasive and osteolytic factors. (PMID:21700681)
• These results point to the existence of an autophagy-stimulatory ‘switch’ whereby TAB2 and TAB3 abandon inhibitory interactions with Beclin 1 to engage in a stimulatory liaison with TAK1. (PMID:22081109)
• human TAB2 and TAB3, ubiquitin-chain sensory proteins involved in NF-kappaB signalling, are directly inactivated by enteropathogenic Escherichia coli NleE, a conserved bacterial type-III-secreted effector responsible for blocking host NF-kappaB signalling (PMID:22158122)
• TAK1 and its adapter protein, TAB2, reciprocally regulate both TAK1- and ASK1-mediated signaling pathways to direct the activations of NF-kappaB and AP-1. (PMID:22167179)
• our data implicate Tab2 as a mediator of resistance to endocrine therapy and as a potential new target to reverse pharmacological resistance and potentiate antiestrogen action. (PMID:22249258)
• MiR-23b suppresses IL-17-, tumor necrosis factor alpha (TNF-alpha)- or IL-1beta-induced NF-kappaB activation and inflammatory cytokine expression by targeting TAB2, TAB3 and IKK-alpha. (PMID:22660635)
• We found that endothelial TAK1 and TAB2, but not TAB1, were critically involved in vascular formation (PMID:22972987)
• These data indicate that overexpression of TRIM22 may negatively regulate the TRAF6-stimulated NF-kappaB pathway by interacting with and degrading TAB2. (PMID:23818111)
• SUMOylation may serve as a novel mechanism for the regulation of TAB2. (PMID:24096733)
• conclude that TRIM38 negatively regulates TNFalpha- and IL-1beta-induced signaling by mediating lysosome-dependent degradation of TAB2/3, two critical components in TNFalpha- and IL-1beta-induced signaling pathways (PMID:24434549)
• Authors demonstrate that enterovirus 71 3C interacts with TAB2 and TAK1 and suppresses cytokine expression via cleavage of the TAK1 complex proteins. (PMID:24942571)
• DK1 inhibits the formation of the TAK1-TAB2-TRAF6 complex and leads to the inhibition of TRAF6 ubiquitination. (PMID:26432169)
• The combination of WES, genomic triangulation, and systems biology has uncovered perturbations in TGF-beta activated kinase 1 signaling as a novel pathogenic substrate for polyvalvular syndrome. (PMID:27452334)
• The expression of miR-155 target gene, TAB2, and the downstream gene, iNOS, were found to be inhibited in psoriatic dermal mesenchymal stem cells. (PMID:27706699)
• A Novel Functional Domain of Tab2 Involved in the Interaction with Estrogen Receptor Alpha in Breast Cancer Cells (PMID:27992601)
• Data suggest that mRNA/protein levels of NLRP6 are down-regulated in synovial tissues and synoviocytes of rheumatoid arthritis (RA) patients compared to osteoarthritis patients; NLRP6 provides docking site to facilitate interaction between TAB2/3 and TRIM38 in RA synoviocytes in response to TNFalpha. (NLRP6 = ; TAB2/3 = transforming growth factor-b-activated kinase 1-binding protein 2/3; TRIM38 = tripartite motif 38) (PMID:28295271)
• Data indicate an association between TAK1-binding protein 2 (TAB2) mutations and a connective tissue disorder with severe polyvalvular heart disease and subtle facial dysmorphism. (PMID:28386937)
• multiple GPCR agonists utilize non-canonical TAB1-TAB2 and TAB1-TAB3-dependent p38 activation to promote endothelial inflammatory responses. (PMID:30760523)
• we deeply dissect the molecular pathogenesis of the TAB2 c.1398dup variant and show that the resulting phenotype is well explained by TAB2 loss-of-function. Our data also offer initial insights on the ECM homeostasis impairment as a molecular mechanism probably underlying a multisystem disorder linked to TAB2. (PMID:31250519)
• rs237028 polymorphism in the TAB2 gene was associated with epithelial ovarian cancer susceptibility in Chinese population. (PMID:31485280)
• A single nucleotide deletion resulting in a frameshift in exon 4 of TAB2 is associated with a polyvalular syndrome. (PMID:31981616)
• Associations between TAB2 gene polymorphisms and dilated cardiomyopathy in a Chinese population. (PMID:32270697)
• lncRNA CASC2 inhibits lipopolysaccharideinduced acute lung injury via miR27b/TAB2 axis. (PMID:33174006)

Cross-species orthologs

3 orthologs

Organism	Symbol	Gene ID
danio_rerio	tab2	ENSDARG00000021509
mus_musculus	Tab2	ENSMUSG00000015755
rattus_norvegicus	Tab2	ENSRNOG00000016054

Paralogs (3): BTF3L4 (ENSG00000134717), BTF3 (ENSG00000145741), TAB3 (ENSG00000157625)

Protein

Protein identifiers

TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 — Q9NYJ8 (reviewed: Q9NYJ8)

Alternative names: Mitogen-activated protein kinase kinase kinase 7-interacting protein 2, TAK1-binding protein 2, TGF-beta-activated kinase 1-binding protein 2

All UniProt accessions (5): A0A1B0GV57, A0A8V8TQR7, Q9NYJ8, U3KQ62, U3KQR0

UniProt curated annotations — full annotation on UniProt →

Function. Adapter required to activate the JNK and NF-kappa-B signaling pathways through the specific recognition of ‘Lys-63’-linked polyubiquitin chains by its RanBP2-type zinc finger (NZF). Acts as an adapter linking MAP3K7/TAK1 and TRAF6 to ‘Lys-63’-linked polyubiquitin chains. The RanBP2-type zinc finger (NZF) specifically recognizes Lys-63’-linked polyubiquitin chains unanchored or anchored to the substrate proteins such as RIPK1/RIP1 and RIPK2: this acts as a scaffold to organize a large signaling complex to promote autophosphorylation of MAP3K7/TAK1, and subsequent activation of I-kappa-B-kinase (IKK) core complex by MAP3K7/TAK1. Also recognizes and binds Lys-63’-linked polyubiquitin chains of heterotypic ‘Lys-63’-/‘Lys-48’-linked branched ubiquitin chains. Regulates the IL1-mediated translocation of NCOR1 out of the nucleus. Involved in heart development.

Subunit / interactions. Interacts with MAP3K7 and TRAF6. Identified in the TRIKA2 complex composed of MAP3K7, TAB1 and TAB2. Binds ‘Lys-63’-linked polyubiquitin chains. Interacts with NCOR1 and HDAC3 to form a ternary complex. Interacts (via C-terminal) with NUMBL (via PTB domain). Interacts (via the C-terminus) with DYNC2I2 (via WD domains). Interacts with RBCK1. Interacts with TRIM5. Interacts with TRIM38 (via B30.2/SPRY domain), leading to its translocation to lysosomes and degradation. Interacts with ASB1; this interaction promotes TAB2 stability.

Subcellular location. Membrane. Endosome membrane. Lysosome membrane. Cytoplasm. Cytosol.

Tissue specificity. Widely expressed. In the embryo, expressed in the ventricular trabeculae, endothelial cells of the conotruncal cushions of the outflow tract and in the endothelial cells lining the developing aortic valves.

Post-translational modifications. Degraded in a lysosome-dependent manner following interaction with TRIM38. SUMOylated by TRIM60; leading to inhibition of MAPK/NF-kappaB activation and the innate immune response. Ubiquitinated; following IL1 stimulation or TRAF6 overexpression. Ubiquitination involves RBCK1 leading to proteasomal degradation. Ubiquitinated at Lys-611 by TRIM45 leading to proteasomal degradation. Phosphorylated. (Microbial infection) Methylated at Cys-673 by enteropathogenic E.coli protein NleE or S.flexneri protein OspZ: methylation disrupts zinc-binding and ability to bind ‘Lys-63’-linked ubiquitin, leading to NF-kappa-B inactivation.

Disease relevance. Congenital heart defects, multiple types, 2 (CHTD2) [MIM:614980] A disease characterized by congenital developmental abnormalities involving structures of the heart. CHTD2 patients have left ventricular outflow tract obstruction, subaortic stenosis, residual aortic regurgitation, atrial fibrillation, bicuspid aortic valve and aortic dilation. The disease is caused by variants affecting the gene represented in this entry. A chromosomal aberration involving TAB2 has been found in a family with congenital heart disease. Translocation t(2;6)(q21;q25).

Domain organisation. The RanBP2-type zinc finger (NZF) mediates binding to two consecutive ‘Lys-63’-linked ubiquitins.

Isoforms (2)

UniProt ID	Names	Canonical?
Q9NYJ8-1	1	yes
Q9NYJ8-2	2

RefSeq proteins (4): NP_001278963, NP_001278964, NP_001356435, NP_055908 (=MANE)

Domains & families (InterPro)

ID	Name	Type
IPR001876	Znf_RanBP2	Domain
IPR003892	CUE	Domain
IPR036443	Znf_RanBP2_sf	Homologous_superfamily
IPR041911	TAB2/3_CUE	Domain

Pfam: PF02845

UniProt features (49 total): mutagenesis site 11, modified residue 7, compositionally biased region 5, region of interest 5, turn 4, cross-link 3, sequence variant 3, helix 3, splice variant 2, chain 1, domain 1, zinc finger region 1, sequence conflict 1, strand 1, coiled-coil region 1

Structure

Experimental structures (PDB)

6 structures.

PDB	Method	Resolution (Å)
2WWZ	X-RAY DIFFRACTION	1.4
9AVT	X-RAY DIFFRACTION	1.5
9AVW	X-RAY DIFFRACTION	1.75
2WX0	X-RAY DIFFRACTION	2.4
2WX1	X-RAY DIFFRACTION	3
2DAE	SOLUTION NMR

Predicted structure (AlphaFold)

Model	pLDDT	Fraction very-high
AF-Q9NYJ8-F1	53.24	0.14

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 (10): 173, 372, 450, 482, 524, 582, 673, 329, 562, 611

Mutagenesis-validated functional residues (11):

Position	Phenotype
329	loss of trim60-mediated sumoylation; when associated with r-562.
562	loss of trim60-mediated sumoylation; when associated with r-329.
611	loss of trim35-mediated ubiquitination.
670	disrupted zinc-finger; abolished methylation at c-673.
673	abolished cys methylation and ability to bind ’lys-63’-linked ubiquitin.
675	abolishes ubiquitin binding.
678	abolishes ubiquitin binding.
681	abolishes ubiquitin binding.
684	disrupted zinc-finger; abolished methylation at c-673.
685	abolishes ubiquitin binding.
687	disrupted zinc-finger; abolished methylation at c-673.

Function

Pathways and Gene Ontology

Reactome pathways

55 pathways

ID	Pathway
R-HSA-1251985	Nuclear signaling by ERBB4
R-HSA-168638	NOD1/2 Signaling Pathway
R-HSA-202424	Downstream TCR signaling
R-HSA-2871837	FCERI mediated NF-kB activation
R-HSA-445989	TAK1-dependent IKK and NF-kappa-B activation
R-HSA-450302	activated TAK1 mediates p38 MAPK activation
R-HSA-450321	JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1
R-HSA-5357956	TNFR1-induced NF-kappa-B signaling pathway
R-HSA-5607764	CLEC7A (Dectin-1) signaling
R-HSA-9014325	TICAM1,TRAF6-dependent induction of TAK1 complex
R-HSA-9020702	Interleukin-1 signaling
R-HSA-937042	IRAK2 mediated activation of TAK1 complex
R-HSA-937072	TRAF6-mediated induction of TAK1 complex within TLR4 complex
R-HSA-9645460	Alpha-protein kinase 1 signaling pathway
R-HSA-9705671	SARS-CoV-2 activates/modulates innate and adaptive immune responses
R-HSA-975163	IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation
R-HSA-1236394	Signaling by ERBB4
R-HSA-1280215	Cytokine Signaling in Immune system
R-HSA-1280218	Adaptive Immune System
R-HSA-162582	Signal Transduction
R-HSA-1643685	Disease
R-HSA-166016	Toll Like Receptor 4 (TLR4) Cascade
R-HSA-166058	MyD88:MAL(TIRAP) cascade initiated on plasma membrane
R-HSA-166166	MyD88-independent TLR4 cascade
R-HSA-168138	Toll Like Receptor 9 (TLR9) Cascade
R-HSA-168142	Toll Like Receptor 10 (TLR10) Cascade
R-HSA-168164	Toll Like Receptor 3 (TLR3) Cascade
R-HSA-168176	Toll Like Receptor 5 (TLR5) Cascade
R-HSA-168179	Toll Like Receptor TLR1:TLR2 Cascade
R-HSA-168181	Toll Like Receptor 7/8 (TLR7/8) Cascade

MSigDB gene sets: 410 (showing top): REACTOME_TRAF6_MEDIATED_INDUCTION_OF_TAK1_COMPLEX_WITHIN_TLR4_COMPLEX, GOBP_REGULATION_OF_AUTOPHAGY, REACTOME_INNATE_IMMUNE_SYSTEM, GOBP_REGULATION_OF_PHOSPHORYLATION, REACTOME_ADAPTIVE_IMMUNE_SYSTEM, REACTOME_NOD1_2_SIGNALING_PATHWAY, REACTOME_CYTOKINE_SIGNALING_IN_IMMUNE_SYSTEM, GOBP_INFLAMMATORY_RESPONSE, GOCC_VACUOLAR_MEMBRANE, NKX25_02, REACTOME_NUCLEOTIDE_BINDING_DOMAIN_LEUCINE_RICH_REPEAT_CONTAINING_RECEPTOR_NLR_SIGNALING_PATHWAYS, KEGG_MAPK_SIGNALING_PATHWAY, TTTGTAG_MIR520D, ATACCTC_MIR202, GOBP_CANONICAL_NF_KAPPAB_SIGNAL_TRANSDUCTION

GO Biological Process (13): inflammatory response (GO:0006954), heart development (GO:0007507), negative regulation of autophagy (GO:0010507), response to lipopolysaccharide (GO:0032496), non-canonical NF-kappaB signal transduction (GO:0038061), defense response to bacterium (GO:0042742), positive regulation of canonical NF-kappaB signal transduction (GO:0043123), positive regulation of protein kinase activity (GO:0045860), canonical NF-kappaB signal transduction (GO:0007249), response to bacterium (GO:0009617), p38MAPK cascade (GO:0038066), negative regulation of canonical NF-kappaB signal transduction (GO:0043124), protein K63-linked ubiquitination (GO:0070534)

GO Molecular Function (6): zinc ion binding (GO:0008270), ubiquitin binding (GO:0043130), molecular adaptor activity (GO:0060090), K63-linked polyubiquitin modification-dependent protein binding (GO:0070530), protein binding (GO:0005515), metal ion binding (GO:0046872)

GO Cellular Component (9): nucleoplasm (GO:0005654), cytoplasm (GO:0005737), lysosomal membrane (GO:0005765), cytosol (GO:0005829), plasma membrane (GO:0005886), endosome membrane (GO:0010008), lysosome (GO:0005764), endosome (GO:0005768), membrane (GO:0016020)

Reactome top-level categories

Rollup of top-18 pathways:

Category	Pathways
MyD88:MAL(TIRAP) cascade initiated on plasma membrane	2
Toll Like Receptor 3 (TLR3) Cascade	2
TRIF (TICAM1)-mediated TLR4 signaling	2
TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation	2
MyD88 cascade initiated on plasma membrane	2
MAP kinase activation	2
Immune System	2
Signaling by ERBB4	1
Nucleotide-binding domain, leucine rich repeat containing receptor (NLR) signaling pathways	1
TCR signaling	1
Fc epsilon receptor (FCERI) signaling	1
Interleukin-1 signaling	1
TNF signaling	1
C-type lectin receptors (CLRs)	1
Interleukin-1 family signaling	1

GO top-level categories

Rollup of top GO terms by namespace:

Category	Terms
cellular anatomical structure	4
defense response	2
intracellular signaling cassette	2
canonical NF-kappaB signal transduction	2
regulation of canonical NF-kappaB signal transduction	2
binding	2
animal organ development	1
circulatory system development	1
autophagy	1
negative regulation of catabolic process	1
regulation of autophagy	1
response to molecule of bacterial origin	1
response to lipid	1
response to oxygen-containing compound	1
response to bacterium	1
positive regulation of intracellular signal transduction	1
positive regulation of protein phosphorylation	1
protein kinase activity	1
positive regulation of kinase activity	1
regulation of protein kinase activity	1
response to other organism	1
MAPK cascade	1
negative regulation of intracellular signal transduction	1
protein polyubiquitination	1
transition metal ion binding	1
ubiquitin-like protein binding	1
molecular_function	1
polyubiquitin modification-dependent protein binding	1
cation binding	1
nuclear lumen	1
intracellular anatomical structure	1
lysosome	1
lytic vacuole membrane	1
cytoplasm	1
membrane	1
cell periphery	1
endosome	1
cytoplasmic vesicle membrane	1
bounding membrane of organelle	1
lytic vacuole	1

Protein interactions and networks

STRING

1982 interactions, top by confidence (×1000):

Protein A	Protein B	Partner UniProt	Score
TAB2	TAB1	Q15750	999
TAB2	MAP3K7	O43318	998
TAB2	TRAF6	Q9Y4K3	998
TAB2	NCOR1	O75376	992
TAB2	TAB3	Q8N5C8	986
TAB2	IKBKG	Q9Y6K9	984
TAB2	RIPK1	Q13546	982
TAB2	IRAK1	P51617	972
TAB2	UBE2N	P61088	936
TAB2	G3V2F7	G3V2F7	927
TAB2	SMAD7	O15105	916
TAB2	MYD88	P78397	911
TAB2	IKBKB	O14920	893
TAB2	IRAK2	O43187	879
TAB2	CHUK	O15111	876

IntAct

223 interactions, top by confidence:

A	B	Type	Score
CTDSP1	CDCA3	psi-mi:“MI:0914”(association)	0.940
MAP3K7	TAB2	psi-mi:“MI:0915”(physical association)	0.920
TAB2	MAP3K7	psi-mi:“MI:0914”(association)	0.920
TAB2	TAB1	psi-mi:“MI:0915”(physical association)	0.910
MAP3K7	TAB1	psi-mi:“MI:0914”(association)	0.900
TAB1	MAP3K7	psi-mi:“MI:0914”(association)	0.900
TAB3	MAP3K7	psi-mi:“MI:0914”(association)	0.830
TIRAP	TLR4	psi-mi:“MI:0914”(association)	0.810
MAP3K7	UBC	psi-mi:“MI:0915”(physical association)	0.740
TAB2	TRAF6	psi-mi:“MI:0915”(physical association)	0.680
TRAF6	TAB2	psi-mi:“MI:0915”(physical association)	0.680
TAB2	CAMK2A	psi-mi:“MI:0915”(physical association)	0.670
FOSL1	TAB2	psi-mi:“MI:0915”(physical association)	0.670
HSP90AA1	CHUK	psi-mi:“MI:0914”(association)	0.670
TAB2	FOSL1	psi-mi:“MI:0915”(physical association)	0.670
HSPA14	DNAJC2	psi-mi:“MI:0914”(association)	0.670
CARNMT1	NUP42	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:0914”(association)	0.640
YWHAG	BLTP3B	psi-mi:“MI:2364”(proximity)	0.640
TNIK	LMP1	psi-mi:“MI:0914”(association)	0.610
YWHAH	PLEKHG3	psi-mi:“MI:0914”(association)	0.610
Map3k7	TAB2	psi-mi:“MI:0701”(dna strand elongation)	0.590
YWHAH	BLTP3B	psi-mi:“MI:0914”(association)	0.570
YWHAH	BLTP3B	psi-mi:“MI:2364”(proximity)	0.570
TNIK	TAB2	psi-mi:“MI:0915”(physical association)	0.560

BioGRID (401): UBC (Reconstituted Complex), UBC (Reconstituted Complex), TAB2 (Reconstituted Complex), TAB2 (Reconstituted Complex), TAB2 (Reconstituted Complex), UBC (Reconstituted Complex), IKBKG (Reconstituted Complex), IRAK1 (Reconstituted Complex), TAB2 (Two-hybrid), TAB2 (Affinity Capture-MS), TAB2 (Affinity Capture-MS), TAB2 (Affinity Capture-MS), TAB2 (Affinity Capture-Western), UBC (Reconstituted Complex), TAB2 (Reconstituted Complex)

ESM2 similar proteins: A1L1N5, A4IIG7, B3NFQ7, B4HKJ7, B4QMP1, B5DF21, O15350, O35711, P23899, P25054, P27889, P35680, P43354, P57094, P57095, P60320, Q03365, Q05192, Q06219, Q07436, Q07917, Q08E53, Q0IHW3, Q59E55, Q5FWP2, Q5PRF9, Q5R5Y4, Q5RER5, Q5U303, Q5ZK36, Q6PD31, Q7ZXH3, Q80XS6, Q8C8U0, Q8CBY1, Q8ND30, Q8SXX4, Q8UW00, Q94071, Q95LV5

Diamond homologs: Q571K4, Q5RFW2, Q5U303, Q7ZXH3, Q8N5C8, Q99K90, Q9NYJ8

SIGNOR signaling

10 interactions.

A	Effect	B	Mechanism
TAB2	“up-regulates activity”	MAP3K7	binding
RIPK1	“up-regulates activity”	TAB2	binding
SMAD7	up-regulates	TAB2	binding
MALT1	up-regulates	TAB2	binding
TAB2	up-regulates	JNK	binding
TAB2	up-regulates	p38	binding
TRAF6	“up-regulates activity”	TAB2	binding

Enriched among interaction partners

Reactome pathways and GO biological processes over-represented among this gene’s 145 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
IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation	7	54.4×	1e-09
TRAF6-mediated induction of TAK1 complex within TLR4 complex	7	51.0×	2e-09
Activation of BAD and translocation to mitochondria	6	46.6×	6e-08
JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1	8	42.4×	7e-10
Chk1/Chk2(Cds1) mediated inactivation of Cyclin B:Cdk1 complex	6	41.1×	1e-07
SARS-CoV-1 targets host intracellular signalling and regulatory pathways	6	41.1×	1e-07
activated TAK1 mediates p38 MAPK activation	8	40.5×	8e-10
Regulation of NF-kappa B signaling	6	38.8×	2e-07

GO biological processes:

GO term	Partners	Fold	FDR
MyD88-dependent toll-like receptor signaling pathway	6	45.3×	1e-06
protein refolding	8	40.3×	2e-08
toll-like receptor 4 signaling pathway	6	25.5×	3e-05
canonical NF-kappaB signal transduction	8	23.6×	9e-07
protein targeting	5	14.8×	2e-03
substantia nigra development	5	14.8×	2e-03
response to unfolded protein	6	14.6×	4e-04
cellular response to type II interferon	8	13.4×	3e-05

Disease & clinical

Clinical variants and AI predictions

ClinVar

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

Classification	Count (floor)
Pathogenic	23
Likely pathogenic	9
Uncertain significance	109
Likely benign	54
Benign	16

Top pathogenic / likely-pathogenic (30)

Variant ID	HGVS	Classification
1048629	NM_001292034.3(TAB2):c.446C>G (p.Ser149Ter)	Pathogenic
1176212	NM_001292034.3(TAB2):c.1719del (p.Arg574fs)	Pathogenic
1460407	NC_000006.11:g.(?149718720)(149720340_?)del	Pathogenic
1802104	NM_001292034.3(TAB2):c.608_609insA (p.Val204fs)	Pathogenic
2441831	NM_001292034.3(TAB2):c.473_474del (p.His158fs)	Pathogenic
2577979	NM_001292034.3(TAB2):c.308dup (p.Thr104fs)	Pathogenic
3246224	NC_000006.11:g.(?149691134)(149700674_?)del	Pathogenic
3253321	NM_001292034.3(TAB2):c.508C>T (p.Gln170Ter)	Pathogenic
3254807	NM_001292034.3(TAB2):c.379C>T (p.Gln127Ter)	Pathogenic
3255071	NM_001292034.3(TAB2):c.363_364insGTTA (p.Phe122fs)	Pathogenic
3255073	NM_001292034.3(TAB2):c.1813_1814delinsC (p.Asp605fs)	Pathogenic
3368828	NM_001292034.3(TAB2):c.542T>G (p.Leu181Ter)	Pathogenic
3724679	NM_001292034.3(TAB2):c.346C>T (p.Gln116Ter)	Pathogenic
373469	NM_001292034.3(TAB2):c.251C>A (p.Ser84Ter)	Pathogenic
4081888	NM_001292034.3(TAB2):c.24del (p.Ile8fs)	Pathogenic
4082552	NM_001292034.3(TAB2):c.49C>T (p.Arg17Ter)	Pathogenic
4085534	NM_001292034.3(TAB2):c.548del (p.Pro183fs)	Pathogenic
4179275	NM_001292034.3(TAB2):c.394C>T (p.Gln132Ter)	Pathogenic
4632541	NM_001292034.3(TAB2):c.366del (p.Gln123fs)	Pathogenic
4711475	NM_001292034.3(TAB2):c.1764+1G>T	Pathogenic
5211	NM_001292034.3(TAB2):c.622C>T (p.Pro208Ser)	Pathogenic
976750	NM_001292034.3(TAB2):c.622_626del (p.Pro208fs)	Pathogenic
985634	NM_001292034.3(TAB2):c.253_254del (p.Gln85fs)	Pathogenic
1708259	NM_001292034.3(TAB2):c.548C>T (p.Pro183Leu)	Likely pathogenic
2631202	NM_001292034.3(TAB2):c.80_84delinsAGG (p.Val27fs)	Likely pathogenic
3064559	NM_001292034.3(TAB2):c.1739C>A (p.Ser580Ter)	Likely pathogenic
3336981	NM_001292034.3(TAB2):c.312_313insAG (p.His105fs)	Likely pathogenic
3357774	NM_001292034.3(TAB2):c.1720C>T (p.Arg574Ter)	Likely pathogenic
372702	NM_001292034.3(TAB2):c.403C>T (p.Gln135Ter)	Likely pathogenic
4293178	NM_001292034.3(TAB2):c.656_660del (p.Ile219fs)	Likely pathogenic

SpliceAI

1967 predictions. Top by Δscore:

Variant	Effect	Δscore
6:149369905:A:AG	acceptor_gain	1.0000
6:149369905:ACAG:A	acceptor_loss	1.0000
6:149369906:C:G	acceptor_gain	1.0000
6:149369907:A:AC	acceptor_loss	1.0000
6:149369907:A:AG	acceptor_gain	1.0000
6:149369908:G:GA	acceptor_gain	1.0000
6:149369908:GA:G	acceptor_gain	1.0000
6:149369908:GAA:G	acceptor_gain	1.0000
6:149369908:GAAA:G	acceptor_gain	1.0000
6:149369908:GAAAA:G	acceptor_gain	1.0000
6:149370096:ACAG:A	donor_loss	1.0000
6:149370097:CAGGT:C	donor_loss	1.0000
6:149370099:GG:G	donor_loss	1.0000
6:149370101:T:G	donor_loss	1.0000
6:149397602:A:AG	acceptor_gain	1.0000
6:149397603:G:GC	acceptor_gain	1.0000
6:149397603:GCT:G	acceptor_gain	1.0000
6:149397603:GCTC:G	acceptor_gain	1.0000
6:149397765:G:GG	donor_gain	1.0000
6:149397964:TTCA:T	acceptor_loss	1.0000
6:149397966:CA:C	acceptor_loss	1.0000
6:149397967:A:AG	acceptor_gain	1.0000
6:149397968:G:GC	acceptor_loss	1.0000
6:149397968:G:GG	acceptor_gain	1.0000
6:149399102:A:AG	acceptor_gain	1.0000
6:149399103:G:GG	acceptor_gain	1.0000
6:149399180:CAAAG:C	donor_loss	1.0000
6:149399181:AAAGG:A	donor_loss	1.0000
6:149399182:AAGG:A	donor_loss	1.0000
6:149399183:AGG:A	donor_loss	1.0000

AlphaMissense

0 scored. Top likely-pathogenic:

dbSNP variants (sampled 300 via entrez): RS1000003897 (6:149405911 G>A), RS1000009 (6:149267031 G>A,C), RS1000027607 (6:149374803 G>C), RS1000035436 (6:149219507 T>C), RS1000037854 (6:149362750 A>G), RS1000041922 (6:149319203 A>G), RS1000056179 (6:149352010 G>C), RS1000073311 (6:149333707 TAGTGTG>T), RS1000098265 (6:149252220 A>G), RS1000106099 (6:149360972 C>T), RS1000107102 (6:149393210 G>A,C), RS1000110049 (6:149369612 C>T), RS1000130535 (6:149230750 G>A,T), RS1000141325 (6:149271137 G>A,T), RS1000170617 (6:149356243 T>C)

Disease associations

OMIM: gene MIM:605101 | disease phenotypes: MIM:614980

GenCC curated gene-disease

Disease	Classification	Inheritance
congenital heart defects, multiple types, 2	Definitive	Autosomal dominant
chromosome 6q24-q25 deletion syndrome	Definitive	Autosomal dominant
polyvalvular heart disease syndrome	Supportive	Autosomal dominant

Mondo (3): congenital heart defects, multiple types, 2 (MONDO:0014000), polyvalvular heart disease syndrome (MONDO:0016460), chromosome 6q24-q25 deletion syndrome (MONDO:0013025)

Orphanet (1): Cardiac anomalies-short stature-joint hypermobility-facial dysmorphism syndrome (Orphanet:228410)

HPO phenotypes

13 total (13 of 13 shown, HPO-id order):

HPO	Term
HP:0000006	Autosomal dominant inheritance
HP:0001629	Ventricular septal defect
HP:0001635	Congestive heart failure
HP:0001636	Tetralogy of Fallot
HP:0001647	Bicuspid aortic valve
HP:0001650	Aortic valve stenosis
HP:0001659	Aortic regurgitation
HP:0001682	Subvalvular aortic stenosis
HP:0003577	Congenital onset
HP:0004764	Myxomatous mitral valve degeneration
HP:0004942	Aortic aneurysm
HP:0005110	Atrial fibrillation
HP:0032092	Left ventricular outflow tract obstruction

GWAS associations

14 associations (top):

Study	Trait	p-value
GCST000080_6	Hemostatic factors and hematological phenotypes	8.000000e-06
GCST001017_2	Diabetic retinopathy	3.000000e-06
GCST001144_2	Dupuytren’s disease	3.000000e-07
GCST001420_1	Breast cancer	4.000000e-12
GCST003043_96	Inflammatory bowel disease	1.000000e-07
GCST003044_48	Crohn’s disease	7.000000e-09
GCST004858_4	Dupuytren’s disease	1.000000e-17
GCST004988_268	Breast cancer	4.000000e-06
GCST008256_10	Diverticulitis	6.000000e-07
GCST010796_1839	Electrocardiogram morphology (amplitude at temporal datapoints)	3.000000e-08
GCST010796_1840	Electrocardiogram morphology (amplitude at temporal datapoints)	7.000000e-09
GCST010866_118	Coronary artery disease	2.000000e-08
GCST90020026_582	Hip index	3.000000e-08
GCST90020028_245	Hip circumference adjusted for BMI	2.000000e-08

EFO canonical traits (4, from GWAS)

EFO ID	Trait name
EFO:0004305	erythrocyte count
EFO:0004229	Dupuytren Contracture
EFO:0004327	electrocardiography
EFO:0008039	BMI-adjusted hip circumference

Drugs & pharmacology

Drug and pharmacology data

Is drug target: yes

ChEMBL targets (1): CHEMBL4295965 (SINGLE PROTEIN)

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

PharmGKB clinical annotations

1 annotations.

Variant	Type	Level	Drugs	Phenotypes
rs577001	Toxicity	3	gefitinib	Diarrhea

PharmGKB variants

4 variants.

Variant	Genes	Level	Score	#Clin annots	Drugs
rs237025	SUMO4, TAB2	3	1.00	1	tacrolimus
rs6942381	TAB2		0.00	0
rs577001	TAB2	3	2.00	1	gefitinib
rs237024	SUMO4, TAB2		0.00	0

CTD chemical–gene interactions

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

Chemical	Actions (top 5)	PubMed papers
Valproic Acid	affects cotreatment, decreases expression, affects expression, increases methylation	6
7,8-Dihydro-7,8-dihydroxybenzo(a)pyrene 9,10-oxide	decreases expression, increases expression	3
trichostatin A	affects cotreatment, decreases expression	2
Particulate Matter	affects response to substance, decreases expression, increases abundance, increases expression	2
aristolochic acid I	decreases expression	1
GSK-J4	increases expression	1
FR900359	decreases phosphorylation	1
triphenyl phosphate	affects expression	1
sodium arsenite	increases expression	1
casticin	decreases expression	1
di-n-butylphosphoric acid	affects expression	1
CGP 52608	affects binding, increases reaction	1
K 7174	increases expression	1
4-(5-benzo(1,3)dioxol-5-yl-4-pyridin-2-yl-1H-imidazol-2-yl)benzamide	affects cotreatment, decreases expression	1
abrine	increases expression	1
dorsomorphin	affects cotreatment, decreases expression	1
asparanin A	decreases expression	1
jinfukang	decreases expression	1
Sunitinib	increases expression	1
Zoledronic Acid	increases expression	1
Leflunomide	increases expression	1
Air Pollutants	affects response to substance, decreases expression, increases abundance, increases expression	1
Arsenic	affects methylation	1
Benzo(a)pyrene	decreases methylation	1
Caffeine	affects phosphorylation	1
Camptothecin	decreases response to substance	1
Chelating Agents	affects binding, increases expression	1
Copper	affects binding, increases expression	1
Coumestrol	decreases expression	1
Methotrexate	increases expression	1

ChEMBL screening assays

1 unique, capped per target: 1 binding

Representative assays (with source publication via chembl_document):

Assay ID	Type	Description	Source paper
CHEMBL4118786	Binding	Binding affinity to TAB2 in human NCI-H23 cells at 1 uM by mass spectrometry based pull down assay	Studies of TAK1-centered polypharmacology with novel covalent TAK1 inhibitors. — Bioorg Med Chem

Cellosaurus cell lines

8 cell lines: 6 cancer cell line, 1 embryonic stem cell, 1 transformed cell line

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

Cellosaurus	Name	Category	Sex
CVCL_D1Z9	Abcam A-549 TAB2 KO	Cancer cell line	Male
CVCL_D6K6	WAe009-A-Z	Embryonic stem cell	Female
CVCL_D8BY	Ubigene A-549 TAB2 KO	Cancer cell line	Male
CVCL_D8WS	Ubigene HCT 116 TAB2 KO	Cancer cell line	Male
CVCL_D9TT	Ubigene HEK293 TAB2 KO	Transformed cell line	Female
CVCL_E0QF	Ubigene HeLa TAB2 KO	Cancer cell line	Female
CVCL_TR43	HAP1 TAB2 (-) 1	Cancer cell line	Male
CVCL_TR44	HAP1 TAB2 (-) 2	Cancer cell line	Male

Clinical trials (associated diseases)

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