Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTH7KRRF)

• DOT Name: Protein jagged-2 (JAG2)
• Synonyms: Jagged2; hJ2
• Gene Name: JAG2
• Related Disease: Muscular dystrophy, limb-girdle, autosomal recessive 27
• UniProt ID: JAG2_HUMAN
• PDB ID: 5MW5; 5MW7; 5MWF
• Pfam ID: PF21700 ; PF01414 ; PF00008 ; PF07645 ; PF12661 ; PF07657
• Sequence:
  MRAQGRGRLPRRLLLLLALWVQAARPMGYFELQLSALRNVNGELLSGACCDGDGRTTRAG
  GCGHDECDTYVRVCLKEYQAKVTPTGPCSYGHGATPVLGGNSFYLPPAGAAGDRARARAR
  AGGDQDPGLVVIPFQFAWPRSFTLIVEAWDWDNDTTPNEELLIERVSHAGMINPEDRWKS
  LHFSGHVAHLELQIRVRCDENYYSATCNKFCRPRNDFFGHYTCDQYGNKACMDGWMGKEC
  KEAVCKQGCNLLHGGCTVPGECRCSYGWQGRFCDECVPYPGCVHGSCVEPWQCNCETNWG
  GLLCDKDLNYCGSHHPCTNGGTCINAEPDQYRCTCPDGYSGRNCEKAEHACTSNPCANGG
  SCHEVPSGFECHCPSGWSGPTCALDIDECASNPCAAGGTCVDQVDGFECICPEQWVGATC
  QLDANECEGKPCLNAFSCKNLIGGYYCDCIPGWKGINCHINVNDCRGQCQHGGTCKDLVN
  GYQCVCPRGFGGRHCELERDECASSPCHSGGLCEDLADGFHCHCPQGFSGPLCEVDVDLC
  EPSPCRNGARCYNLEGDYYCACPDDFGGKNCSVPREPCPGGACRVIDGCGSDAGPGMPGT
  AASGVCGPHGRCVSQPGGNFSCICDSGFTGTYCHENIDDCLGQPCRNGGTCIDEVDAFRC
  FCPSGWEGELCDTNPNDCLPDPCHSRGRCYDLVNDFYCACDDGWKGKTCHSREFQCDAYT
  CSNGGTCYDSGDTFRCACPPGWKGSTCAVAKNSSCLPNPCVNGGTCVGSGASFSCICRDG
  WEGRTCTHNTNDCNPLPCYNGGICVDGVNWFRCECAPGFAGPDCRINIDECQSSPCAYGA
  TCVDEINGYRCSCPPGRAGPRCQEVIGFGRSCWSRGTPFPHGSSWVEDCNSCRCLDGRRD
  CSKVWCGWKPCLLAGQPEALSAQCPLGQRCLEKAPGQCLRPPCEAWGECGAEEPPSTPCL
  PRSGHLDNNCARLTLHFNRDHVPQGTTVGAICSGIRSLPATRAVARDRLLVLLCDRASSG
  ASAVEVAVSFSPARDLPDSSLIQGAAHAIVAAITQRGNSSLLLAVTEVKVETVVTGGSST
  GLLVPVLCGAFSVLWLACVVLCVWWTRKRRKERERSRLPREESANNQWAPLNPIRNPIER
  PGGHKDVLYQCKNFTPPPRRADEALPGPAGHAAVREDEEDEDLGRGEEDSLEAEKFLSHK
  FTKDPGRSPGRPAHWASGPKVDNRAVRSINEARYAGKE
• Function: Putative Notch ligand involved in the mediation of Notch signaling. Involved in limb development.
• Tissue Specificity: Expressed in heart, placenta and skeletal muscle and to a lesser extent in pancreas. Very low expression in brain, lung, liver and kidney.
• KEGG Pathway:
  Endocrine resistance (hsa01522)
  Notch sig.ling pathway (hsa04330)
  Th1 and Th2 cell differentiation (hsa04658)
  Pathways in cancer (hsa05200)
  Breast cancer (hsa05224)
• Reactome Pathway:
  Constitutive Signaling by NOTCH1 PEST Domain Mutants (R-HSA-2644606)
  Constitutive Signaling by NOTCH1 t(7 (R-HSA-2660826)
  Constitutive Signaling by NOTCH1 HD Domain Mutants (R-HSA-2691232)
  Constitutive Signaling by NOTCH1 HD+PEST Domain Mutants (R-HSA-2894862)
  NOTCH2 Activation and Transmission of Signal to the Nucleus (R-HSA-2979096)
  NOTCH3 Activation and Transmission of Signal to the Nucleus (R-HSA-9013507)
  M1580_K2555) Translocation Mutant (9)(NOTCH1)
  Activated NOTCH1 Transmits Signal to the Nucleus (R-HSA-2122948)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Muscular dystrophy, limb-girdle, autosomal recessive 27	DISTYAGN	Strong	Autosomal recessive	[1]

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 Protein jagged-2 (JAG2).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein jagged-2 (JAG2).	[5]

9 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 Protein jagged-2 (JAG2).	[3]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Protein jagged-2 (JAG2).	[4]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Protein jagged-2 (JAG2).	[6]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Protein jagged-2 (JAG2).	[7]
Enzalutamide	DMGL19D	Approved	Enzalutamide affects the expression of Protein jagged-2 (JAG2).	[8]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Protein jagged-2 (JAG2).	[9]
PEITC	DMOMN31	Phase 2	PEITC increases the expression of Protein jagged-2 (JAG2).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Protein jagged-2 (JAG2).	[11]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Protein jagged-2 (JAG2).	[12]

References

• [1] A form of muscular dystrophy associated with pathogenic variants in JAG2. Am J Hum Genet. 2021 May 6;108(5):840-856. doi: 10.1016/j.ajhg.2021.03.020. Epub 2021 Apr 15.
• [2] 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.
• [3] Gamma-irradiation and doxorubicin treatment of normal human cells cause cell cycle arrest via different pathways. Mol Cells. 2005 Dec 31;20(3):331-8.
• [4] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [5] 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.
• [6] Arsenic trioxide inhibits the proliferation of myeloma cell line through notch signaling pathway. Cancer Cell Int. 2013 Mar 13;13(1):25. doi: 10.1186/1475-2867-13-25.
• [7] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [8] NOTCH signaling is activated in and contributes to resistance in enzalutamide-resistant prostate cancer cells. J Biol Chem. 2019 May 24;294(21):8543-8554. doi: 10.1074/jbc.RA118.006983. Epub 2019 Apr 2.
• [9] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [10] Notch activation by phenethyl isothiocyanate attenuates its inhibitory effect on prostate cancer cell migration. PLoS One. 2011;6(10):e26615. doi: 10.1371/journal.pone.0026615. Epub 2011 Oct 24.
• [11] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [12] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.