Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTL9YH7V)

• DOT Name: Junctophilin-2 (JPH2)
• Synonyms: JP-2; Junctophilin type 2
• Gene Name: JPH2
• Related Disease:
  Atrial fibrillation
  Cardiac failure
  Cardiovascular disease
  Congestive heart failure
  Dilated cardiomyopathy 1A
  Familial hypertrophic cardiomyopathy
  Hypertrophic cardiomyopathy 17
  Myocardial infarction
  Pulmonary arterial hypertension
  Cardiomyopathy
  Dilated cardiomyopathy
  Hypertrophic cardiomyopathy
  Cardiac disease
  Cardiomyopathy, dilated, 2E
  Systolic heart failure
• UniProt ID: JPH2_HUMAN
• PDB ID: 7RXE; 7RXQ
• Pfam ID: PF02493
• Sequence:
  MSGGRFDFDDGGAYCGGWEGGKAHGHGLCTGPKGQGEYSGSWNFGFEVAGVYTWPSGNTF
  EGYWSQGKRHGLGIETKGRWLYKGEWTHGFKGRYGIRQSSSSGAKYEGTWNNGLQDGYGT
  ETYADGGTYQGQFTNGMRHGYGVRQSVPYGMAVVVRSPLRTSLSSLRSEHSNGTVAPDSP
  ASPASDGPALPSPAIPRGGFALSLLANAEAAARAPKGGGLFQRGALLGKLRRAESRTSVG
  SQRSRVSFLKSDLSSGASDAASTASLGEAAEGADEAAPFEADIDATTTETYMGEWKNDKR
  SGFGVSERSSGLRYEGEWLDNLRHGYGCTTLPDGHREEGKYRHNVLVKDTKRRMLQLKSN
  KVRQKVEHSVEGAQRAAAIARQKAEIAASRTSHAKAKAEAAEQAALAANQESNIARTLAR
  ELAPDFYQPGPEYQKRRLLQEILENSESLLEPPDRGAGAAGLPQPPRESPQLHERETPRP
  EGGSPSPAGTPPQPKRPRPGVSKDGLLSPGAWNGEPSGEGSRSVTPSEGAGRRSPARPAT
  ERMAIEALQAPPAPSREPEVALYQGYHSYAVRTTPPEPPPFEDQPEPEVSGSESAPSSPA
  TAPLQAPTLRGPEPARETPAKLEPKPIIPKAEPRAKARKTEARGLTKAGAKKKARKEAAL
  AAEAEVEVEEVPNTILICMVILLNIGLAILFVHLLT
• Function: [Junctophilin-2]: Membrane-binding protein that provides a structural bridge between the plasma membrane and the sarcoplasmic reticulum and is required for normal excitation-contraction coupling in cardiomyocytes. Provides a structural foundation for functional cross-talk between the cell surface and intracellular Ca(2+) release channels by maintaining the 12-15 nm gap between the sarcolemma and the sarcoplasmic reticulum membranes in the cardiac dyads. Necessary for proper intracellular Ca(2+) signaling in cardiac myocytes via its involvement in ryanodine receptor-mediated calcium ion release. Contributes to the construction of skeletal muscle triad junctions; [Junctophilin-2 N-terminal fragment]: Transcription repressor required to safeguard against the deleterious effects of cardiac stress. Generated following cleavage of the Junctophilin-2 chain by calpain in response to cardiac stress in cardiomyocytes. Following cleavage and release from the membrane, translocates to the nucleus, binds DNA and represses expression of genes implicated in cell growth and differentiation, hypertrophy, inflammation and fibrosis. Modifies the transcription profile and thereby attenuates pathological remodeling in response to cardiac stress. Probably acts by competing with MEF2 transcription factors and TATA-binding proteins.
• Tissue Specificity: Specifically expressed in skeletal muscle and heart.

Molecular Interaction Atlas (MIA) of This DOT

15 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Atrial fibrillation	DIS15W6U	Strong	Biomarker	[1]
Cardiac failure	DISDC067	Strong	Biomarker	[2]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[3]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[2]
Dilated cardiomyopathy 1A	DIS0RK9Z	Strong	Genetic Variation	[4]
Familial hypertrophic cardiomyopathy	DISQ89HN	Strong	ModifyingMutation	[5]
Hypertrophic cardiomyopathy 17	DISH2941	Strong	Autosomal dominant	[6]
Myocardial infarction	DIS655KI	Strong	Biomarker	[7]
Pulmonary arterial hypertension	DISP8ZX5	Strong	Biomarker	[8]
Cardiomyopathy	DISUPZRG	moderate	Altered Expression	[6]
Dilated cardiomyopathy	DISX608J	Moderate	Semidominant	[9]
Hypertrophic cardiomyopathy	DISQG2AI	Moderate	Autosomal dominant	[9]
Cardiac disease	DISVO1I5	Limited	Genetic Variation	[10]
Cardiomyopathy, dilated, 2E	DISS01ZQ	Limited	Unknown	[11]
Systolic heart failure	DISSFU1K	Limited	Genetic Variation	[10]

2 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 Junctophilin-2 (JPH2).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Junctophilin-2 (JPH2).	[19]

8 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 Junctophilin-2 (JPH2).	[13]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Junctophilin-2 (JPH2).	[14]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Junctophilin-2 (JPH2).	[15]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Junctophilin-2 (JPH2).	[16]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of Junctophilin-2 (JPH2).	[17]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate increases the expression of Junctophilin-2 (JPH2).	[18]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 increases the expression of Junctophilin-2 (JPH2).	[20]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane decreases the expression of Junctophilin-2 (JPH2).	[21]

References

• [1] The Transcription Factor ETV1 Induces Atrial Remodeling and Arrhythmia.Circ Res. 2018 Aug 17;123(5):550-563. doi: 10.1161/CIRCRESAHA.118.313036.
• [2] RBFox2-miR-34a-Jph2 axis contributes to cardiac decompensation during heart failure.Proc Natl Acad Sci U S A. 2019 Mar 26;116(13):6172-6180. doi: 10.1073/pnas.1822176116. Epub 2019 Mar 13.
• [3] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [4] Analysis of enriched rare variants in JPH2-encoded junctophilin-2 among Greater Middle Eastern individuals reveals a novel homozygous variant associated with neonatal dilated cardiomyopathy.Sci Rep. 2019 Jun 21;9(1):9038. doi: 10.1038/s41598-019-44987-6.
• [5] T-tubule remodeling during transition from hypertrophy to heart failure.Circ Res. 2010 Aug 20;107(4):520-31. doi: 10.1161/CIRCRESAHA.109.212324. Epub 2010 Jun 24.
• [6] Mutations in JPH2-encoded junctophilin-2 associated with hypertrophic cardiomyopathy in humans. J Mol Cell Cardiol. 2007 Jun;42(6):1026-35. doi: 10.1016/j.yjmcc.2007.04.006. Epub 2007 Apr 18.
• [7] Post-Myocardial Infarction T-tubules Form Enlarged Branched Structures With Dysregulation of Junctophilin-2 and Bridging Integrator 1 (BIN-1).J Am Heart Assoc. 2017 May 4;6(5):e004834. doi: 10.1161/JAHA.116.004834.
• [8] Colchicine Depolymerizes Microtubules, Increases Junctophilin-2, and Improves Right Ventricular Function in Experimental Pulmonary Arterial Hypertension.J Am Heart Assoc. 2017 May 31;6(6):e006195. doi: 10.1161/JAHA.117.006195.
• [9] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [10] Heterozygous junctophilin-2 (JPH2) p.(Thr161Lys) is a monogenic cause for HCM with heart failure.PLoS One. 2018 Sep 20;13(9):e0203422. doi: 10.1371/journal.pone.0203422. eCollection 2018.
• [11] Mutation in JPH2 cause dilated cardiomyopathy. Clin Genet. 2016 Nov;90(5):468-469. doi: 10.1111/cge.12825. Epub 2016 Jul 29.
• [12] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [15] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Cannabidiol enhances cytotoxicity of anti-cancer drugs in human head and neck squamous cell carcinoma. Sci Rep. 2020 Nov 26;10(1):20622. doi: 10.1038/s41598-020-77674-y.
• [18] CXCL14 downregulation in human keratinocytes is a potential biomarker for a novel in vitro skin sensitization test. Toxicol Appl Pharmacol. 2020 Jan 1;386:114828. doi: 10.1016/j.taap.2019.114828. Epub 2019 Nov 14.
• [19] 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.
• [20] Loss of TRIM33 causes resistance to BET bromodomain inhibitors through MYC- and TGF-beta-dependent mechanisms. Proc Natl Acad Sci U S A. 2016 Aug 2;113(31):E4558-66.
• [21] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.