Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO8E77P)

• DOT Name: Jerky protein homolog (JRK)
• Gene Name: JRK
• Related Disease:
  Stomach cancer
  Absence seizure
  Advanced cancer
  Bladder cancer
  Colorectal carcinoma
  Epithelial ovarian cancer
  Familial adenomatous polyposis
  Gastric cancer
  Juvenile myoclonic epilepsy
  Nasopharyngeal carcinoma
  Ovarian cancer
  Ovarian neoplasm
  Temporal lobe epilepsy
  Urinary bladder cancer
  Absence epilepsy
  Duodenal ulcer
  Gastric adenocarcinoma
  Epilepsy
  Non-insulin dependent diabetes
  Epilepsy, idiopathic generalized
• UniProt ID: JERKY_HUMAN
• Pfam ID: PF04218 ; PF03184 ; PF03221
• Sequence:
  MASKPAAGKSRGEKRKRVVLTLKEKIDICTRLEKGESRKALMQEYNVGMSTLYDIRAHKA
  QLLRFFASSDSNKALEQRRTLHTPKLEHLDRVLYEWFLGKRSEGVPVSGPMLIEKAKDFY
  EQMQLTEPCVFSGGWLWRFKARHGIKKLDASSEKQSADHQAAEQFCAFFRSLAAEHGLSA
  EQVYNADETGLFWRCLPNPTPEGGAVPGPKQGKDRLTVLMCANATGSHRLKPLAIGKCSG
  PRAFKGIQHLPVAYKAQGNAWVDKEIFSDWFHHIFVPSVREHFRTIGLPEDSKAVLLLDS
  SRAHPQEAELVSSNVFTIFLPASVASLVQPMEQGIRRDFMRNFINPPVPLQGPHARYNMN
  DAIFSVACAWNAVPSHVFRRAWRKLWPSVAFAEGSSSEEELEAECFPVKPHNKSFAHILE
  LVKEGSSCPGQLRQRQAASWGVAGREAEGGRPPAATSPAEVVWSSEKTPKADQDGRGDPG
  EGEEVAWEQAAVAFDAVLRFAERQPCFSAQEVGQLRALRAVFRSQQQETVGLEDVVVTSP
  EELAIPKCCLEASTET
• Function: May bind DNA.
• Tissue Specificity: Expressed ubiquitously.

Molecular Interaction Atlas (MIA) of This DOT

20 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Stomach cancer	DISKIJSX	Definitive	Genetic Variation	[1]
Absence seizure	DIS4709R	Strong	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[3]
Bladder cancer	DISUHNM0	Strong	Genetic Variation	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[3]
Familial adenomatous polyposis	DISW53RE	Strong	Biomarker	[3]
Gastric cancer	DISXGOUK	Strong	Biomarker	[5]
Juvenile myoclonic epilepsy	DISYXV1N	Strong	Biomarker	[2]
Nasopharyngeal carcinoma	DISAOTQ0	Strong	Genetic Variation	[6]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[7]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[3]
Temporal lobe epilepsy	DISNOPXX	Strong	Biomarker	[8]
Urinary bladder cancer	DISDV4T7	Strong	Genetic Variation	[9]
Absence epilepsy	DISJPOUD	moderate	Biomarker	[2]
Duodenal ulcer	DISNHHCN	moderate	Genetic Variation	[10]
Gastric adenocarcinoma	DISWWLTC	moderate	Genetic Variation	[11]
Epilepsy	DISBB28L	Disputed	Biomarker	[12]
Non-insulin dependent diabetes	DISK1O5Z	Disputed	Biomarker	[13]
Epilepsy, idiopathic generalized	DISODZC9	Limited	Genetic Variation	[2]

3 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 Jerky protein homolog (JRK).	[14]
TAK-243	DM4GKV2	Phase 1	TAK-243 increases the sumoylation of Jerky protein homolog (JRK).	[21]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of Jerky protein homolog (JRK).	[22]

7 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 Jerky protein homolog (JRK).	[15]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Jerky protein homolog (JRK).	[16]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Jerky protein homolog (JRK).	[17]
Sodium lauryl sulfate	DMLJ634	Approved	Sodium lauryl sulfate affects the expression of Jerky protein homolog (JRK).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Jerky protein homolog (JRK).	[19]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Jerky protein homolog (JRK).	[20]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A affects the expression of Jerky protein homolog (JRK).	[23]

References

• [1] Genome-wide association study identifies gastric cancer susceptibility loci at 12q24.11-12 and 20q11.21.Cancer Sci. 2018 Dec;109(12):4015-4024. doi: 10.1111/cas.13815. Epub 2018 Oct 31.
• [2] Polymorphism analysis of JRK/JH8, the human homologue of mouse jerky, and description of a rare mutation in a case of CAE evolving to JME.Epilepsy Res. 2001 Aug;46(2):157-67. doi: 10.1016/s0920-1211(01)00275-3.
• [3] JRK is a positive regulator of -catenin transcriptional activity commonly overexpressed in colon, breast and ovarian cancer.Oncogene. 2016 Jun 2;35(22):2834-41. doi: 10.1038/onc.2015.347. Epub 2015 Oct 12.
• [4] Genome-wide association study identifies multiple loci associated with bladder cancer risk.Hum Mol Genet. 2014 Mar 1;23(5):1387-98. doi: 10.1093/hmg/ddt519. Epub 2013 Oct 24.
• [5] Association of high-evidence gastric cancer susceptibility loci and somatic gene expression levels with survival.Carcinogenesis. 2017 Oct 26;38(11):1119-1128. doi: 10.1093/carcin/bgx090.
• [6] A genome-wide association study of nasopharyngeal carcinoma identifies three new susceptibility loci.Nat Genet. 2010 Jul;42(7):599-603. doi: 10.1038/ng.601. Epub 2010 May 30.
• [7] Intestinal stem cell overproliferation resulting from inactivation of the APC tumor suppressor requires the transcription cofactors Earthbound and Erect wing.PLoS Genet. 2017 Jul 14;13(7):e1006870. doi: 10.1371/journal.pgen.1006870. eCollection 2017 Jul.
• [8] The RNA binding domain of Jerky consists of tandemly arranged helix-turn-helix/homeodomain-like motifs and binds specific sets of mRNAs.Mol Cell Biol. 2003 Jun;23(12):4083-93. doi: 10.1128/MCB.23.12.4083-4093.2003.
• [9] A multi-stage genome-wide association study of bladder cancer identifies multiple susceptibility loci.Nat Genet. 2010 Nov;42(11):978-84. doi: 10.1038/ng.687. Epub 2010 Oct 24.
• [10] A genome-wide association study identifies two susceptibility loci for duodenal ulcer in the Japanese population.Nat Genet. 2012 Mar 4;44(4):430-4, S1-2. doi: 10.1038/ng.1109.
• [11] Loss-of-function variants in ATM confer risk of gastric cancer.Nat Genet. 2015 Aug;47(8):906-10. doi: 10.1038/ng.3342. Epub 2015 Jun 22.
• [12] JH8, a gene highly homologous to the mouse jerky gene, maps to the region for childhood absence epilepsy on 8q24.Biochem Biophys Res Commun. 1998 Jul 20;248(2):307-14. doi: 10.1006/bbrc.1998.8947.
• [13] Nightshift work, chronotype, and genome-wide DNA methylation in blood.Epigenetics. 2017;12(10):833-840. doi: 10.1080/15592294.2017.1366407. Epub 2017 Nov 27.
• [14] 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.
• [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] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [17] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [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] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [21] 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.
• [22] 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.
• [23] A trichostatin A expression signature identified by TempO-Seq targeted whole transcriptome profiling. PLoS One. 2017 May 25;12(5):e0178302. doi: 10.1371/journal.pone.0178302. eCollection 2017.