Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUH7VMO)

• DOT Name: Junction plakoglobin (JUP)
• Synonyms: Catenin gamma; Desmoplakin III; Desmoplakin-3
• Gene Name: JUP
• Related Disease:
  Arrhythmogenic right ventricular dysplasia 12
  Inherited epidermolysis bullosa
  Naxos disease
  Lethal acantholytic epidermolysis bullosa
• UniProt ID: PLAK_HUMAN
• PDB ID: 3IFQ
• Pfam ID: PF00514
• Sequence:
  MEVMNLMEQPIKVTEWQQTYTYDSGIHSGANTCVPSVSSKGIMEEDEACGRQYTLKKTTT
  YTQGVPPSQGDLEYQMSTTARAKRVREAMCPGVSGEDSSLLLATQVEGQATNLQRLAEPS
  QLLKSAIVHLINYQDDAELATRALPELTKLLNDEDPVVVTKAAMIVNQLSKKEASRRALM
  GSPQLVAAVVRTMQNTSDLDTARCTTSILHNLSHHREGLLAIFKSGGIPALVRMLSSPVE
  SVLFYAITTLHNLLLYQEGAKMAVRLADGLQKMVPLLNKNNPKFLAITTDCLQLLAYGNQ
  ESKLIILANGGPQALVQIMRNYSYEKLLWTTSRVLKVLSVCPSNKPAIVEAGGMQALGKH
  LTSNSPRLVQNCLWTLRNLSDVATKQEGLESVLKILVNQLSVDDVNVLTCATGTLSNLTC
  NNSKNKTLVTQNSGVEALIHAILRAGDKDDITEPAVCALRHLTSRHPEAEMAQNSVRLNY
  GIPAIVKLLNQPNQWPLVKATIGLIRNLALCPANHAPLQEAAVIPRLVQLLVKAHQDAQR
  HVAAGTQQPYTDGVRMEEIVEGCTGALHILARDPMNRMEIFRLNTIPLFVQLLYSSVENI
  QRVAAGVLCELAQDKEAADAIDAEGASAPLMELLHSRNEGTATYAAAVLFRISEDKNPDY
  RKRVSVELTNSLFKHDPAAWEAAQSMIPINEPYGDDMDATYRPMYSSDVPLDPLEMHMDM
  DGDYPIDTYSDGLRPPYPTADHMLA
• Function: Common junctional plaque protein. The membrane-associated plaques are architectural elements in an important strategic position to influence the arrangement and function of both the cytoskeleton and the cells within the tissue. The presence of plakoglobin in both the desmosomes and in the intermediate junctions suggests that it plays a central role in the structure and function of submembranous plaques. Acts as a substrate for VE-PTP and is required by it to stimulate VE-cadherin function in endothelial cells. Can replace beta-catenin in E-cadherin/catenin adhesion complexes which are proposed to couple cadherins to the actin cytoskeleton.
• Tissue Specificity: Expressed in the heart (at protein level).
• KEGG Pathway:
  Cytoskeleton in muscle cells (hsa04820)
  Pathways in cancer (hsa05200)
  Transcriptio.l misregulation in cancer (hsa05202)
  Acute myeloid leukemia (hsa05221)
  Gastric cancer (hsa05226)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
• Reactome Pathway:
  VEGFR2 mediated vascular permeability (R-HSA-5218920)
  Neutrophil degranulation (R-HSA-6798695)
  Keratinization (R-HSA-6805567)
  Formation of the cornified envelope (R-HSA-6809371)
  RHOA GTPase cycle (R-HSA-8980692)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RHOQ GTPase cycle (R-HSA-9013406)
  RHOH GTPase cycle (R-HSA-9013407)
  RHOJ GTPase cycle (R-HSA-9013409)
  Regulation of CDH11 function (R-HSA-9762292)
  Regulation of CDH19 Expression and Function (R-HSA-9764302)
  CDH11 homotypic and heterotypic interactions (R-HSA-9833576)
  Adherens junctions interactions (R-HSA-418990)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arrhythmogenic right ventricular dysplasia 12	DISOKP5T	Strong	Autosomal dominant	[1]
Inherited epidermolysis bullosa	DIS3PBSM	Strong	Autosomal recessive	[2]
Naxos disease	DISL5ZUP	Strong	Autosomal recessive	[2]
Lethal acantholytic epidermolysis bullosa	DISZRB2P	Supportive	Autosomal recessive	[3]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Junction plakoglobin (JUP).	[4]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Junction plakoglobin (JUP).	[5]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Junction plakoglobin (JUP).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Junction plakoglobin (JUP).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Junction plakoglobin (JUP).	[8]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Junction plakoglobin (JUP).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Junction plakoglobin (JUP).	[10]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Junction plakoglobin (JUP).	[13]
Decitabine	DMQL8XJ	Approved	Decitabine increases the expression of Junction plakoglobin (JUP).	[14]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Junction plakoglobin (JUP).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Junction plakoglobin (JUP).	[17]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Junction plakoglobin (JUP).	[18]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Junction plakoglobin (JUP).	[9]
GSK2110183	DMZHB37	Phase 2	GSK2110183 increases the expression of Junction plakoglobin (JUP).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Junction plakoglobin (JUP).	[21]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Junction plakoglobin (JUP).	[22]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Junction plakoglobin (JUP).	[23]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Junction plakoglobin (JUP).	[24]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Junction plakoglobin (JUP).	[25]

6 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 Junction plakoglobin (JUP).	[11]
Quercetin	DM3NC4M	Approved	Quercetin decreases the phosphorylation of Junction plakoglobin (JUP).	[12]
Fulvestrant	DM0YZC6	Approved	Fulvestrant increases the methylation of Junction plakoglobin (JUP).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Junction plakoglobin (JUP).	[20]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Junction plakoglobin (JUP).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Junction plakoglobin (JUP).	[15]

References

• [1] Identification of a deletion in plakoglobin in arrhythmogenic right ventricular cardiomyopathy with palmoplantar keratoderma and woolly hair (Naxos disease). Lancet. 2000 Jun 17;355(9221):2119-24. doi: 10.1016/S0140-6736(00)02379-5.
• [2] 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.
• [3] Lack of plakoglobin leads to lethal congenital epidermolysis bullosa: a novel clinico-genetic entity. Hum Mol Genet. 2011 May 1;20(9):1811-9. doi: 10.1093/hmg/ddr064. Epub 2011 Feb 14.
• [4] 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.
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• [7] 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.
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• [9] Convergent transcriptional profiles induced by endogenous estrogen and distinct xenoestrogens in breast cancer cells. Carcinogenesis. 2006 Aug;27(8):1567-78.
• [10] 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.
• [11] 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.
• [12] 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.
• [13] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [14] Epigenetic regulation of human trophoblastic cell migration and invasion. Endocrinology. 2006 Nov;147(11):5275-83. doi: 10.1210/en.2006-0288. Epub 2006 Aug 3.
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• [16] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] A novel long noncoding RNA AK001796 acts as an oncogene and is involved in cell growth inhibition by resveratrol in lung cancer. Toxicol Appl Pharmacol. 2015 Jun 1;285(2):79-88.
• [19] Novel ATP-competitive Akt inhibitor afuresertib suppresses the proliferation of malignant pleural mesothelioma cells. Cancer Med. 2017 Nov;6(11):2646-2659. doi: 10.1002/cam4.1179. Epub 2017 Sep 27.
• [20] 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.
• [21] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [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] Activin/nodal signaling switches the terminal fate of human embryonic stem cell-derived trophoblasts. J Biol Chem. 2015 Apr 3;290(14):8834-48.
• [24] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [25] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.