Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPM6F85)

• DOT Name: TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1)
• Synonyms: Mitogen-activated protein kinase kinase kinase 7-interacting protein 1; TGF-beta-activated kinase 1-binding protein 1; TAK1-binding protein 1
• Gene Name: TAB1
• Related Disease:
  Breast neoplasm
  Epithelial ovarian cancer
  Malignant thymoma
  Neoplasm
  Non-small-cell lung cancer
  Ovarian cancer
  Ovarian neoplasm
  Polycystic ovarian syndrome
  Systemic sclerosis
  Thyroid gland papillary carcinoma
  Triple negative breast cancer
  Bacterial infection
  Coronary atherosclerosis
  Myocardial ischemia
  Asthma
• UniProt ID: TAB1_HUMAN
• PDB ID: 2J4O; 2POM; 2POP; 2YDS; 2YIY; 4AY5; 4AY6; 4GS6; 4KA3; 4L3P; 4L52; 4L53; 4O91; 5DIY; 5E7R; 5GJD; 5GJF; 5GJG; 5J7S; 5J8I; 5J9L; 5JGA; 5JGB; 5JGD; 5JH6; 5JK3; 5NZZ; 5O90; 5V5N; 5VVU; 7NTH; 7NTI; 8GW3
• Pfam ID: PF00481
• Sequence:
  MAAQRRSLLQSEQQPSWTDDLPLCHLSGVGSASNRSYSADGKGTESHPPEDSWLKFRSEN
  NCFLYGVFNGYDGNRVTNFVAQRLSAELLLGQLNAEHAEADVRRVLLQAFDVVERSFLES
  IDDALAEKASLQSQLPEGVPQHQLPPQYQKILERLKTLEREISGGAMAVVAVLLNNKLYV
  ANVGTNRALLCKSTVDGLQVTQLNVDHTTENEDELFRLSQLGLDAGKIKQVGIICGQEST
  RRIGDYKVKYGYTDIDLLSAAKSKPIIAEPEIHGAQPLDGVTGFLVLMSEGLYKALEAAH
  GPGQANQEIAAMIDTEFAKQTSLDAVAQAVVDRVKRIHSDTFASGGERARFCPRHEDMTL
  LVRNFGYPLGEMSQPTPSPAPAAGGRVYPVSVPYSSAQSTSKTSVTLSLVMPSQGQMVNG
  AHSASTLDEATPTLTNQSPTLTLQSTNTHTQSSSSSSDGGLFRSRPAHSLPPGEDGRVEP
  YVDFAEFYRLWSVDHGEQSVVTAP
• Function: Key adapter protein that plays an essential role in JNK and NF-kappa-B activation and proinflammatory cytokines production in response to stimulation with TLRs and cytokines. Mechanistically, associates with the catalytic domain of MAP3K7/TAK1 to trigger MAP3K7/TAK1 autophosphorylation leading to its full activation. Similarly, associates with MAPK14 and triggers its autophosphorylation and subsequent activation. In turn, MAPK14 phosphorylates TAB1 and inhibits MAP3K7/TAK1 activation in a feedback control mechanism. Plays also a role in recruiting MAPK14 to the TAK1 complex for the phosphorylation of the TAB2 and TAB3 regulatory subunits.
• Tissue Specificity: Ubiquitous.
• 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)
  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)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  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)
  Ub-specific processing proteases (R-HSA-5689880)
  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)
  NOD1/2 Signaling Pathway (R-HSA-168638)

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast neoplasm	DISNGJLM	Strong	Biomarker	[1]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[2]
Malignant thymoma	DIS59MOU	Strong	Biomarker	[3]
Neoplasm	DISZKGEW	Strong	Altered Expression	[4]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[5]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[2]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[2]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Biomarker	[6]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[7]
Thyroid gland papillary carcinoma	DIS48YMM	Strong	Biomarker	[8]
Triple negative breast cancer	DISAMG6N	Strong	Altered Expression	[9]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[10]
Coronary atherosclerosis	DISKNDYU	moderate	Genetic Variation	[11]
Myocardial ischemia	DISFTVXF	moderate	Genetic Variation	[11]
Asthma	DISW9QNS	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1).	[13]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1).	[14]
Obeticholic acid	DM3Q1SM	Approved	Obeticholic acid decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1).	[15]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1).	[17]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1).	[18]

1 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Manganese	DMKT129	Investigative	Manganese affects the binding of TGF-beta-activated kinase 1 and MAP3K7-binding protein 1 (TAB1).	[19]

References

• [1] Altered TAB1:I kappaB kinase interaction promotes transforming growth factor beta-mediated nuclear factor-kappaB activation during breast cancer progression.Cancer Res. 2008 Mar 1;68(5):1462-70. doi: 10.1158/0008-5472.CAN-07-3094.
• [2] NF-B1, c-Rel, and ELK1 inhibit miR-134 expression leading to TAB1 upregulation in paclitaxel-resistant human ovarian cancer.Oncotarget. 2017 Apr 11;8(15):24853-24868. doi: 10.18632/oncotarget.15267.
• [3] Povidone-iodine results in rapid killing of thymic epithelial tumour cells through cellular fixation?"Lee HS. Lo EM
• [4] Targeting of TGF--activated protein kinase 1 inhibits chemokine (C-C motif) receptor 7 expression, tumor growth and metastasis in breast cancer.Oncotarget. 2015 Jan 20;6(2):995-1007. doi: 10.18632/oncotarget.2739.
• [5] icroRNA?89 plays a suppressive role in cell proliferation and invasion by directly targeting TAB1 in nonsmall cell lung cancer.Mol Med Rep. 2019 Jul;20(1):261-269. doi: 10.3892/mmr.2019.10245. Epub 2019 May 15.
• [6] Progesterone resistance in PCOS endometrium: a microarray analysis in clomiphene citrate-treated and artificial menstrual cycles.J Clin Endocrinol Metab. 2011 Jun;96(6):1737-46. doi: 10.1210/jc.2010-2600. Epub 2011 Mar 16.
• [7] MiR-29a reduces TIMP-1 production by dermal fibroblasts via targeting TGF- activated kinase 1 binding protein 1, implications for systemic sclerosis.PLoS One. 2014 Dec 30;9(12):e115596. doi: 10.1371/journal.pone.0115596. eCollection 2014.
• [8] MiR-758-3p regulates papillary thyroid cancer cell proliferation and migration by targeting TAB1.Pharmazie. 2019 Apr 1;74(4):235-238. doi: 10.1691/ph.2019.8933.
• [9] Dual-target MDM2/MDMX inhibitor increases the sensitization of doxorubicin and inhibits migration and invasion abilities of triple-negative breast cancer cells through activation of TAB1/TAK1/p38 MAPK pathway.Cancer Biol Ther. 2019;20(5):617-632. doi: 10.1080/15384047.2018.1539290. Epub 2018 Nov 21.
• [10] Shrimp TAB1 interacts with TAK1 and p38 and activates the host innate immune response to bacterial infection.Mol Immunol. 2017 Aug;88:10-19. doi: 10.1016/j.molimm.2017.05.016. Epub 2017 May 31.
• [11] The TAB1-p38 complex aggravates myocardial injury and can be targeted by small molecules.JCI Insight. 2018 Aug 23;3(16):e121144. doi: 10.1172/jci.insight.121144. eCollection 2018 Aug 23.
• [12] TLR-related pathway analysis: novel gene-gene interactions in the development of asthma and atopy.Allergy. 2010 Feb;65(2):199-207. doi: 10.1111/j.1398-9995.2009.02111.x. Epub 2009 Nov 25.
• [13] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [14] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [15] Pharmacotoxicology of clinically-relevant concentrations of obeticholic acid in an organotypic human hepatocyte system. Toxicol In Vitro. 2017 Mar;39:93-103.
• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] 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.
• [18] 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.
• [19] TAK1-binding protein 1 is a pseudophosphatase. Biochem J. 2006 Nov 1;399(3):427-34. doi: 10.1042/BJ20061077.