Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTC8WL2V)

• DOT Name: Latent-transforming growth factor beta-binding protein 4 (LTBP4)
• Synonyms: LTBP-4
• Gene Name: LTBP4
• Related Disease:
  Muscular dystrophy
  Adenocarcinoma
  Bloom syndrome
  Breast neoplasm
  Carcinoma
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies
  Dilated cardiomyopathy 1A
  Melanoma
  Myopathy
  Neoplasm
  Scleroderma
  Systemic sclerosis
  Breast cancer
  Breast carcinoma
  Abdominal aortic aneurysm
  Carcinoma of esophagus
  Dilated cardiomyopathy
  Duchenne muscular dystrophy
  Esophageal cancer
  Glioblastoma multiforme
  Neoplasm of esophagus
  Pulmonary fibrosis
  Squamous cell carcinoma
• UniProt ID: LTBP4_HUMAN
• Pfam ID: PF07645 ; PF12661 ; PF00683
• Sequence:
  MPRPGTSGRRPLLLVLLLPLFAAATSAASPSPSPSQVVEVPGVPSRPASVAVCRCCPGQT
  SRRSRCIRAFCRVRSCQPKKCAGPQRCLNPVPAVPSPSPSVRKRQVSLNWQPLTLQEARA
  LLKRRRPRGPGGRGLLRRRPPQRAPAGKAPVLCPLICHNGGVCVKPDRCLCPPDFAGKFC
  QLHSSGARPPAPAVPGLTRSVYTMPLANHRDDEHGVASMVSVHVEHPQEASVVVHQVERV
  SGPWEEADAEAVARAEAAARAEAAAPYTVLAQSAPREDGYSDASGFGYCFRELRGGECAS
  PLPGLRTQEVCCRGAGLAWGVHDCQLCSERLGNSERVSAPDGPCPTGFERVNGSCEDVDE
  CATGGRCQHGECANTRGGYTCVCPDGFLLDSSRSSCISQHVISEAKGPCFRVLRDGGCSL
  PILRNITKQICCCSRVGKAWGRGCQLCPPFGSEGFREICPAGPGYHYSASDLRYNTRPLG
  QEPPRVSLSQPRTLPATSRPSAGFLPTHRLEPRPEPRPDPRPGPELPLPSIPAWTGPEIP
  ESGPSSGMCQRNPQVCGPGRCISRPSGYTCACDSGFRLSPQGTRCIDVDECRRVPPPCAP
  GRCENSPGSFRCVCGPGFRAGPRAAECLDVDECHRVPPPCDLGRCENTPGSFLCVCPAGY
  QAAPHGASCQDVDECTQSPGLCGRGACKNLPGSFRCVCPAGFRGSACEEDVDECAQEPPP
  CGPGRCDNTAGSFHCACPAGFRSRGPGAPCQDVDECARSPPPCTYGRCENTEGSFQCVCP
  MGFQPNTAGSECEDVDECENHLACPGQECVNSPGSFQCRTCPSGHHLHRGRCTDVDECSS
  GAPPCGPHGHCTNTEGSFRCSCAPGYRAPSGRPGPCADVNECLEGDFCFPHGECLNTDGS
  FACTCAPGYRPGPRGASCLDVDECSEEDLCQSGICTNTDGSFECICPPGHRAGPDLASCL
  DVDECRERGPALCGSQRCENSPGSYRCVRDCDPGYHAGPEGTCDDVDECQEYGPEICGAQ
  RCENTPGSYRCTPACDPGYQPTPGGGCQDVDECRNRSFCGAHAVCQNLPGSFQCLCDQGY
  EGARDGRHCVDVNECETLQGVCGAALCENVEGSFLCVCPNSPEEFDPMTGRCVPPRTSAG
  TFPGSQPQAPASPVLPARPPPPPLPRRPSTPRQGPVGSGRRECYFDTAAPDACDNILARN
  VTWQECCCTVGEGWGSGCRIQQCPGTETAEYQSLCPHGRGYLAPSGDLSLRRDVDECQLF
  RDQVCKSGVCVNTAPGYSCYCSNGYYYHTQRLECIDNDECADEEPACEGGRCVNTVGSYH
  CTCEPPLVLDGSQRRCVSNESQSLDDNLGVCWQEVGADLVCSHPRLDRQATYTECCCLYG
  EAWGMDCALCPAQDSDDFEALCNVLRPPAYSPPRPGGFGLPYEYGPDLGPPYQGLPYGPE
  LYPPPALPYDPYPPPPGPFARREAPYGAPRFDMPDFEDDGGPYGESEAPAPPGPGTRWPY
  RSRDTRRSFPEPEEPPEGGSYAGSLAEPYEELEAEECGILDGCTNGRCVRVPEGFTCRCF
  DGYRLDMTRMACVDINECDEAEAASPLCVNARCLNTDGSFRCICRPGFAPTHQPHHCAPA
  RPRA
• Function: Key regulator of transforming growth factor beta (TGFB1, TGFB2 and TGFB3) that controls TGF-beta activation by maintaining it in a latent state during storage in extracellular space. Associates specifically via disulfide bonds with the Latency-associated peptide (LAP), which is the regulatory chain of TGF-beta, and regulates integrin-dependent activation of TGF-beta.
• Tissue Specificity: Highly expressed in heart, skeletal muscle, pancreas, uterus, and small intestine. Weakly expressed in placenta and lung.
• Reactome Pathway:
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Muscular dystrophy	DISJD6P7	Definitive	Biomarker	[1]
Adenocarcinoma	DIS3IHTY	Strong	Altered Expression	[2]
Bloom syndrome	DISKXQ7J	Strong	Altered Expression	[3]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[4]
Carcinoma	DISH9F1N	Strong	Altered Expression	[5]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[6]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[7]
Cutis laxa with severe pulmonary, gastrointestinal and urinary anomalies	DISETCW9	Strong	Autosomal recessive	[8]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[9]
Melanoma	DIS1RRCY	Strong	Biomarker	[10]
Myopathy	DISOWG27	Strong	Biomarker	[11]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Scleroderma	DISVQ342	Strong	Biomarker	[3]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[3]
Breast cancer	DIS7DPX1	moderate	Altered Expression	[4]
Breast carcinoma	DIS2UE88	moderate	Altered Expression	[4]
Abdominal aortic aneurysm	DISD06OF	Limited	Genetic Variation	[12]
Carcinoma of esophagus	DISS6G4D	Limited	Altered Expression	[2]
Dilated cardiomyopathy	DISX608J	Limited	Biomarker	[13]
Duchenne muscular dystrophy	DISRQ3NV	Limited	Biomarker	[1]
Esophageal cancer	DISGB2VN	Limited	Altered Expression	[2]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[14]
Neoplasm of esophagus	DISOLKAQ	Limited	Altered Expression	[2]
Pulmonary fibrosis	DISQKVLA	Limited	Biomarker	[3]
Squamous cell carcinoma	DISQVIFL	Limited	Altered Expression	[2]

10 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 Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin affects the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[16]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[17]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[18]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[16]
Selenium	DM25CGV	Approved	Selenium increases the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[19]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[20]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[21]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[24]

3 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 increases the methylation of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[22]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Latent-transforming growth factor beta-binding protein 4 (LTBP4).	[25]

References

• [1] Non-Glycanated Biglycan and LTBP4: Leveraging the extracellular matrix for Duchenne Muscular Dystrophy therapeutics.Matrix Biol. 2018 Aug;68-69:616-627. doi: 10.1016/j.matbio.2018.02.016. Epub 2018 Feb 23.
• [2] Latent transforming growth factor -binding protein 4 is downregulated in esophageal cancer via promoter methylation.PLoS One. 2013 May 31;8(5):e65614. doi: 10.1371/journal.pone.0065614. Print 2013.
• [3] Increased expression of latent TGF--binding protein 4 affects the fibrotic process in scleroderma by TGF-/SMAD signaling.Lab Invest. 2017 May;97(5):591-601. doi: 10.1038/labinvest.2017.20. Epub 2017 Mar 6.
• [4] Versican G1 and G3 domains are upregulated and latent transforming growth factor- binding protein-4 is downregulated in breast cancer stroma.Breast Cancer. 2012 Jan;19(1):46-53. doi: 10.1007/s12282-011-0264-7. Epub 2011 Apr 20.
• [5] Latent transforming growth factor binding protein 4 (LTBP4) is downregulated in mouse and human DCIS and mammary carcinomas.Cell Oncol (Dordr). 2011 Oct;34(5):419-34. doi: 10.1007/s13402-011-0023-y. Epub 2011 Apr 6.
• [6] Genetic association analysis of functional impairment in chronic obstructive pulmonary disease.Am J Respir Crit Care Med. 2006 May 1;173(9):977-84. doi: 10.1164/rccm.200509-1452OC. Epub 2006 Feb 2.
• [7] Polymorphisms in the transforming growth factor beta 1 pathway in relation to colorectal cancer progression.Genes Chromosomes Cancer. 2010 Mar;49(3):270-81. doi: 10.1002/gcc.20738.
• [8] 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.
• [9] Genetic Modifiers of Duchenne Muscular Dystrophy and Dilated Cardiomyopathy.PLoS One. 2015 Oct 29;10(10):e0141240. doi: 10.1371/journal.pone.0141240. eCollection 2015.
• [10] Sequence and expression of a novel member (LTBP-4) of the family of latent transforming growth factor-beta binding proteins.FEBS Lett. 1997 Jul 14;411(2-3):164-8. doi: 10.1016/s0014-5793(97)00685-6.
• [11] Overexpression of Latent TGF Binding Protein 4 in Muscle Ameliorates Muscular Dystrophy through Myostatin and TGF.PLoS Genet. 2016 May 5;12(5):e1006019. doi: 10.1371/journal.pgen.1006019. eCollection 2016 May.
• [12] Assessment of the association between genetic polymorphisms in transforming growth factor beta, and its binding protein (LTBP), and the presence, and expansion, of Abdominal Aortic Aneurysm.Atherosclerosis. 2010 Apr;209(2):367-73. doi: 10.1016/j.atherosclerosis.2009.09.073. Epub 2009 Oct 15.
• [13] Genotype-Specific Interaction of Latent TGF Binding Protein 4 with TGF.PLoS One. 2016 Feb 26;11(2):e0150358. doi: 10.1371/journal.pone.0150358. eCollection 2016.
• [14] Clonal evolution of glioblastoma under therapy.Nat Genet. 2016 Jul;48(7):768-76. doi: 10.1038/ng.3590. Epub 2016 Jun 6.
• [15] 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.
• [16] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [17] 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.
• [18] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [19] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [20] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [21] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [22] 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.
• [23] Inhibiting ubiquitination causes an accumulation of SUMOylated newly synthesized nuclear proteins at PML bodies. J Biol Chem. 2019 Oct 18;294(42):15218-15234. doi: 10.1074/jbc.RA119.009147. Epub 2019 Jul 8.
• [24] 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.
• [25] DNA methylome-wide alterations associated with estrogen receptor-dependent effects of bisphenols in breast cancer. Clin Epigenetics. 2019 Oct 10;11(1):138. doi: 10.1186/s13148-019-0725-y.