Details of Drug Off-Target (DOT)

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

DOT Name Thrombospondin type-1 domain-containing protein 4 (THSD4)
Synonyms A disintegrin and metalloproteinase with thrombospondin motifs-like protein 6; ADAMTS-like protein 6; ADAMTSL-6
Gene Name THSD4
Related Disease
Alzheimer disease ( )
Aortic aneurysm, familial thoracic 12 ( )
Chronic obstructive pulmonary disease ( )
Drug dependence ( )
Non-insulin dependent diabetes ( )
Substance abuse ( )
Substance dependence ( )
Familial thoracic aortic aneurysm and aortic dissection ( )
Osteoporosis ( )
UniProt ID
THSD4_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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Pfam ID
PF19236 ; PF05986 ; PF08686 ; PF19030 ; PF00090
Sequence
MVSHFMGSLSVLCFLLLLGFQFVCPQPSTQHRKVPQRMAAEGAPEDDGGGGAPGVWGAWG
PWSACSRSCSGGVMEQTRPCLPRSYRLRGGQRPGAPARAFADHVVSAVRTSVPLHRSRDE
TPALAGTDASRQGPTVLRGSRHPQPQGLEVTGDRRSRTRGTIGPGKYGYGKAPYILPLQT
DTAHTPQRLRRQKLSSRHSRSQGASSARHGYSSPAHQVPQHGPLYQSDSGPRSGLQAAEA
PIYQLPLTHDQGYPAASSLFHSPETSNNHGVGTHGATQSFSQPARSTAISCIGAYRQYKL
CNTNVCPESSRSIREVQCASYNNKPFMGRFYEWEPFAEVKGNRKCELNCQAMGYRFYVRQ
AEKVIDGTPCDQNGTAICVSGQCKSIGCDDYLGSDKVVDKCGVCGGDNTGCQVVSGVFKH
ALTSLGYHRVVEIPEGATKINITEMYKSNNYLALRSRSGRSIINGNWAIDRPGKYEGGGT
MFTYKRPNEISSTAGESFLAEGPTNEILDVYMIHQQPNPGVHYEYVIMGTNAISPQVPPH
RRPGEPFNGQMVTEGRSQEEGEQKGRNEEKEDLRGEAPEMFTSESAQTFPVRHPDRFSPH
RPDNLVPPAPQPPRRSRDHNWKQLGTTECSTTCGKGSQYPIFRCVHRSTHEEAPESYCDS
SMKPTPEEEPCNIFPCPAFWDIGEWSECSKTCGLGMQHRQVLCRQVYANRSLTVQPYRCQ
HLEKPETTSTCQLKICSEWQIRTDWTSCSVPCGVGQRTRDVKCVSNIGDVVDDEECNMKL
RPNDIENCDMGPCAKSWFLTEWSERCSAECGAGVRTRSVVCMTNHVSSLPLEGCGNNRPA
EATPCDNGPCTGKVEWFAGSWSQCSIECGSGTQQREVICVRKNADTFEVLDPSECSFLEK
PPSQQSCHLKPCGAKWFSTEWSMCSKSCQGGFRVREVRCLSDDMTLSNLCDPQLKPEERE
SCNPQDCVPEVDENCKDKYYNCNVVVQARLCVYNYYKTACCASCTRVANRQTGFLGSR
Function
Promotes FBN1 matrix assembly. Attenuates TGFB signaling, possibly by accelerating the sequestration of large latent complexes of TGFB or active TGFB by FBN1 microfibril assembly, thereby negatively regulating the expression of TGFB regulatory targets, such as POSTN.
KEGG Pathway
TGF-beta sig.ling pathway (hsa04350 )
Reactome Pathway
O-glycosylation of TSR domain-containing proteins (R-HSA-5173214 )
Defective B3GALTL causes PpS (R-HSA-5083635 )

Molecular Interaction Atlas (MIA) of This DOT

9 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Alzheimer disease DISF8S70 Strong Genetic Variation [1]
Aortic aneurysm, familial thoracic 12 DISYOLDK Strong Autosomal dominant [2]
Chronic obstructive pulmonary disease DISQCIRF Strong Genetic Variation [3]
Drug dependence DIS9IXRC Strong Biomarker [4]
Non-insulin dependent diabetes DISK1O5Z Strong Genetic Variation [5]
Substance abuse DIS327VW Strong Biomarker [4]
Substance dependence DISDRAAR Strong Biomarker [4]
Familial thoracic aortic aneurysm and aortic dissection DIS069FB Moderate Autosomal dominant [2]
Osteoporosis DISF2JE0 Limited Genetic Variation [6]
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⏷ Show the Full List of 9 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
17 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Valproate DMCFE9I Approved Valproate increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [7]
Ciclosporin DMAZJFX Approved Ciclosporin increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [8]
Tretinoin DM49DUI Approved Tretinoin increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [9]
Doxorubicin DMVP5YE Approved Doxorubicin decreases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [10]
Cisplatin DMRHGI9 Approved Cisplatin decreases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [11]
Calcitriol DM8ZVJ7 Approved Calcitriol increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [13]
Progesterone DMUY35B Approved Progesterone increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [14]
Folic acid DMEMBJC Approved Folic acid decreases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [15]
Permethrin DMZ0Q1G Approved Permethrin decreases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [16]
Melphalan DMOLNHF Approved Melphalan decreases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [17]
Rifampicin DM5DSFZ Approved Rifampicin increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [18]
SNDX-275 DMH7W9X Phase 3 SNDX-275 increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [19]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene affects the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [20]
(+)-JQ1 DM1CZSJ Phase 1 (+)-JQ1 decreases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [21]
PMID28460551-Compound-2 DM4DOUB Patented PMID28460551-Compound-2 increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [22]
Bisphenol A DM2ZLD7 Investigative Bisphenol A increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [23]
Coumestrol DM40TBU Investigative Coumestrol increases the expression of Thrombospondin type-1 domain-containing protein 4 (THSD4). [24]
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⏷ Show the Full List of 17 Drug(s)
1 Drug(s) Affected the Post-Translational Modifications of This DOT
Drug Name Drug ID Highest Status Interaction REF
Arsenic DMTL2Y1 Approved Arsenic affects the methylation of Thrombospondin type-1 domain-containing protein 4 (THSD4). [12]
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References

1 Family-based association analyses of imputed genotypes reveal genome-wide significant association of Alzheimer's disease with OSBPL6, PTPRG, and PDCL3.Mol Psychiatry. 2016 Nov;21(11):1608-1612. doi: 10.1038/mp.2015.218. Epub 2016 Feb 2.
2 Pathogenic variants in THSD4, encoding the ADAMTS-like 6 protein, predispose to inherited thoracic aortic aneurysm. Genet Med. 2021 Jan;23(1):111-122. doi: 10.1038/s41436-020-00947-4. Epub 2020 Aug 28.
3 Genetic landscape of chronic obstructive pulmonary disease identifies heterogeneous cell-type and phenotype associations.Nat Genet. 2019 Mar;51(3):494-505. doi: 10.1038/s41588-018-0342-2. Epub 2019 Feb 25.
4 Genome wide association for addiction: replicated results and comparisons of two analytic approaches.PLoS One. 2010 Jan 21;5(1):e8832. doi: 10.1371/journal.pone.0008832.
5 Genome-wide association analysis identifies loci for type 2 diabetes and triglyceride levels.Science. 2007 Jun 1;316(5829):1331-6. doi: 10.1126/science.1142358. Epub 2007 Apr 26.
6 Identification of genes for complex diseases using integrated analysis of multiple types of genomic data.PLoS One. 2012;7(9):e42755. doi: 10.1371/journal.pone.0042755. Epub 2012 Sep 5.
7 The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
8 Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
9 Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
10 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.
11 Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
12 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.
13 Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
14 Progesterone rise on HCG day in GnRH antagonist/rFSH stimulated cycles affects endometrial gene expression. Reprod Biomed Online. 2011 Mar;22(3):263-71. doi: 10.1016/j.rbmo.2010.11.002. Epub 2010 Nov 13.
15 Folic acid supplementation dysregulates gene expression in lymphoblastoid cells--implications in nutrition. Biochem Biophys Res Commun. 2011 Sep 9;412(4):688-92. doi: 10.1016/j.bbrc.2011.08.027. Epub 2011 Aug 16.
16 Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
17 Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 17.
18 Integrated analysis of rifampicin-induced microRNA and gene expression changes in human hepatocytes. Drug Metab Pharmacokinet. 2014;29(4):333-40.
19 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.
20 Influence of cell cycle on responses of MCF-7 cells to benzo[a]pyrene. BMC Genomics. 2011 Jun 29;12:333.
21 CCAT1 is an enhancer-templated RNA that predicts BET sensitivity in colorectal cancer. J Clin Invest. 2016 Feb;126(2):639-52.
22 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.
23 Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
24 Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.