Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPZK76F)

• DOT Name: TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2)
• Synonyms: Mitogen-activated protein kinase kinase kinase 7-interacting protein 2; TAK1-binding protein 2; TAB-2; TGF-beta-activated kinase 1-binding protein 2
• Gene Name: TAB2
• Related Disease:
  Chromosome 6q24-q25 deletion syndrome
  Ectodermal dysplasia
  Asthma
  Autoimmune disease
  Breast cancer
  Breast carcinoma
  Cardiac disease
  Cardiomyopathy
  Congenital heart defects, multiple types, 2
  Connective tissue disorder
  Ehlers-Danlos syndrome
  Graves disease
  Liposarcoma
  Polycystic ovarian syndrome
  Pulmonary disease
  Type-1 diabetes
  X-linked hypohidrotic ectodermal dysplasia
  Crohn disease
  Frontometaphyseal dysplasia
  Inflammatory bowel disease
  Polyvalvular heart disease syndrome
  Rheumatoid arthritis
  Systolic heart failure
  Tetralogy of fallot
• UniProt ID: TAB2_HUMAN
• PDB ID: 2DAE; 2WWZ; 2WX0; 2WX1
• Pfam ID: PF02845
• Sequence:
  MAQGSHQIDFQVLHDLRQKFPEVPEVVVSRCMLQNNNNLDACCAVLSQESTRYLYGEGDL
  NFSDDSGISGLRNHMTSLNLDLQSQNIYHHGREGSRMNGSRTLTHSISDGQLQGGQSNSE
  LFQQEPQTAPAQVPQGFNVFGMSSSSGASNSAPHLGFHLGSKGTSSLSQQTPRFNPIMVT
  LAPNIQTGRNTPTSLHIHGVPPPVLNSPQGNSIYIRPYITTPGGTTRQTQQHSGWVSQFN
  PMNPQQVYQPSQPGPWTTCPASNPLSHTSSQQPNQQGHQTSHVYMPISSPTTSQPPTIHS
  SGSSQSSAHSQYNIQNISTGPRKNQIEIKLEPPQRNNSSKLRSSGPRTSSTSSSVNSQTL
  NRNQPTVYIAASPPNTDELMSRSQPKVYISANAATGDEQVMRNQPTLFISTNSGASAASR
  NMSGQVSMGPAFIHHHPPKSRAIGNNSATSPRVVVTQPNTKYTFKITVSPNKPPAVSPGV
  VSPTFELTNLLNHPDHYVETENIQHLTDPTLAHVDRISETRKLSMGSDDAAYTQALLVHQ
  KARMERLQRELEIQKKKLDKLKSEVNEMENNLTRRRLKRSNSISQIPSLEEMQQLRSCNR
  QLQIDIDCLTKEIDLFQARGPHFNPSAIHNFYDNIGFVGPVPPKPKDQRSIIKTPKTQDT
  EDDEGAQWNCTACTFLNHPALIRCEQCEMPRHF
• 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. Regulates the IL1-mediated translocation of NCOR1 out of the nucleus. Involved in heart development.
• 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.
• KEGG Pathway:
  MAPK sig.ling pathway (hsa04010)
  NF-kappa B sig.ling pathway (hsa04064)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  IL-17 sig.ling pathway (hsa04657)
  TNF sig.ling pathway (hsa04668)
  Alcoholic liver disease (hsa04936)
  Pathogenic Escherichia coli infection (hsa05130)
  Shigellosis (hsa05131)
  Salmonella infection (hsa05132)
  Yersinia infection (hsa05135)
  Leishmaniasis (hsa05140)
  Toxoplasmosis (hsa05145)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  NOD1/2 Signaling Pathway (R-HSA-168638)
  Downstream TCR signaling (R-HSA-202424)
  FCERI mediated NF-kB activation (R-HSA-2871837)
  TAK1-dependent IKK and NF-kappa-B activation (R-HSA-445989)
  activated TAK1 mediates p38 MAPK activation (R-HSA-450302)
  JNK (c-Jun kinases) phosphorylation and activation mediated by activated human TAK1 (R-HSA-450321)
  TNFR1-induced NF-kappa-B signaling pathway (R-HSA-5357956)
  CLEC7A (Dectin-1) signaling (R-HSA-5607764)
  TICAM1,TRAF6-dependent induction of TAK1 complex (R-HSA-9014325)
  Interleukin-1 signaling (R-HSA-9020702)
  IRAK2 mediated activation of TAK1 complex (R-HSA-937042)
  TRAF6-mediated induction of TAK1 complex within TLR4 complex (R-HSA-937072)
  Alpha-protein kinase 1 signaling pathway (R-HSA-9645460)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  IRAK2 mediated activation of TAK1 complex upon TLR7/8 or 9 stimulation (R-HSA-975163)
  Nuclear signaling by ERBB4 (R-HSA-1251985)

Molecular Interaction Atlas (MIA) of This DOT

24 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chromosome 6q24-q25 deletion syndrome	DISORHM4	Definitive	Autosomal dominant	[1]
Ectodermal dysplasia	DISLRS4M	Definitive	Biomarker	[2]
Asthma	DISW9QNS	Strong	Biomarker	[3]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Biomarker	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Cardiac disease	DISVO1I5	Strong	Genetic Variation	[7]
Cardiomyopathy	DISUPZRG	Strong	Genetic Variation	[8]
Congenital heart defects, multiple types, 2	DISU2NC3	Strong	Autosomal dominant	[9]
Connective tissue disorder	DISKXBS3	Strong	Genetic Variation	[7]
Ehlers-Danlos syndrome	DISSVBRR	Strong	Genetic Variation	[7]
Graves disease	DISU4KOQ	Strong	Biomarker	[4]
Liposarcoma	DIS8IZVM	Strong	Altered Expression	[10]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[11]
Pulmonary disease	DIS6060I	Strong	Biomarker	[3]
Type-1 diabetes	DIS7HLUB	Strong	Genetic Variation	[12]
X-linked hypohidrotic ectodermal dysplasia	DISST0XM	Strong	Biomarker	[13]
Crohn disease	DIS2C5Q8	moderate	Genetic Variation	[14]
Frontometaphyseal dysplasia	DISXFPAW	moderate	Genetic Variation	[15]
Inflammatory bowel disease	DISGN23E	moderate	Genetic Variation	[14]
Polyvalvular heart disease syndrome	DIS3YBB9	Supportive	Autosomal dominant	[7]
Rheumatoid arthritis	DISTSB4J	Limited	Genetic Variation	[16]
Systolic heart failure	DISSFU1K	Limited	Genetic Variation	[17]
Tetralogy of fallot	DISMHFNW	Limited	Biomarker	[18]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Camptothecin	DM6CHNJ	Phase 3	TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2) decreases the response to substance of Camptothecin.	[30]

4 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[20]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[27]

7 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[21]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[22]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[25]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[28]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 2 (TAB2).	[29]

References

• [1] Haploinsufficiency of TAB2 causes congenital heart defects in humans. Am J Hum Genet. 2010 Jun 11;86(6):839-49. doi: 10.1016/j.ajhg.2010.04.011. Epub 2010 May 20.
• [2] [New genes candidates for ectodermal dysplasia: TAB2, TRAF6 and TAK1].Med Sci (Paris). 2006 Mar;22(3):229-30. doi: 10.1051/medsci/2006223229.
• [3] Overexpression of miR-155-5p Inhibits the Proliferation and Migration of IL-13-Induced Human Bronchial Smooth Muscle Cells by Suppressing TGF--Activated Kinase 1/MAP3K7-Binding Protein 2.Allergy Asthma Immunol Res. 2018 May;10(3):260-267. doi: 10.4168/aair.2018.10.3.260.
• [4] Contribution of single nucleotide polymorphisms within FCRL3 and MAP3K7IP2 to the pathogenesis of Graves' disease.J Clin Endocrinol Metab. 2006 Mar;91(3):1056-61. doi: 10.1210/jc.2005-1634. Epub 2005 Dec 29.
• [5] A Novel Functional Domain of Tab2 Involved in the Interaction with Estrogen Receptor Alpha in Breast Cancer Cells.PLoS One. 2016 Dec 19;11(12):e0168639. doi: 10.1371/journal.pone.0168639. eCollection 2016.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] A recognizable systemic connective tissue disorder with polyvalvular heart dystrophy and dysmorphism associated with TAB2 mutations. Clin Genet. 2018 Jan;93(1):126-133. doi: 10.1111/cge.13032. Epub 2017 Aug 21.
• [8] Protein molecular modeling techniques investigating novel TAB2 variant R347X causing cardiomyopathy and congenital heart defects in multigenerational family.Mol Genet Genomic Med. 2018 Apr 26;6(4):666-72. doi: 10.1002/mgg3.401. Online ahead of print.
• [9] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [10] Genomic profiling of bone and soft tissue tumors with supernumerary ring chromosomes using tiling resolution bacterial artificial chromosome microarrays.Oncogene. 2006 Nov 9;25(53):7106-16. doi: 10.1038/sj.onc.1209693. Epub 2006 May 29.
• [11] Differential gene expression in granulosa cells from polycystic ovary syndrome patients with and without insulin resistance: identification of susceptibility gene sets through network analysis.J Clin Endocrinol Metab. 2012 Oct;97(10):E2016-21. doi: 10.1210/jc.2011-3441. Epub 2012 Aug 17.
• [12] Functional variants in SUMO4, TAB2, and NFkappaB and the risk of type 1 diabetes.Genes Immun. 2005 May;6(3):231-5. doi: 10.1038/sj.gene.6364174.
• [13] TAB2, TRAF6 and TAK1 are involved in NF-kappaB activation induced by the TNF-receptor, Edar and its adaptator Edaradd.Hum Mol Genet. 2005 Dec 1;14(23):3751-7. doi: 10.1093/hmg/ddi405. Epub 2005 Oct 26.
• [14] Association analyses identify 38 susceptibility loci for inflammatory bowel disease and highlight shared genetic risk across populations.Nat Genet. 2015 Sep;47(9):979-986. doi: 10.1038/ng.3359. Epub 2015 Jul 20.
• [15] A novel MAP3K7 splice mutation causes cardiospondylocarpofacial syndrome with features of hereditary connective tissue disorder.Eur J Hum Genet. 2018 Apr;26(4):582-586. doi: 10.1038/s41431-017-0079-x. Epub 2018 Feb 21.
• [16] SUMO4 and MAP3K7IP2 single nucleotide polymorphisms and susceptibility to rheumatoid arthritis.J Rheumatol. 2006 Jun;33(6):1048-51.
• [17] 6q25.1 (TAB2) microdeletion syndrome: Congenital heart defects and cardiomyopathy.Am J Med Genet A. 2017 Jul;173(7):1848-1857. doi: 10.1002/ajmg.a.38254. Epub 2017 May 2.
• [18] Familial TAB2 microdeletion and congenital heart defects including unusual valve dysplasia and tetralogy of fallot.Am J Med Genet A. 2015 Nov;167A(11):2702-6. doi: 10.1002/ajmg.a.37210. Epub 2015 Jul 2.
• [19] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [20] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [21] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [22] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [23] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [24] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [25] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [26] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [27] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [28] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [29] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [30] ATR inhibitors VE-821 and VX-970 sensitize cancer cells to topoisomerase i inhibitors by disabling DNA replication initiation and fork elongation responses. Cancer Res. 2014 Dec 1;74(23):6968-79.