Details of Drug Off-Target (DOT)

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

• DOT Name: Junctional adhesion molecule-like (JAML)
• Synonyms: Adhesion molecule interacting with CXADR antigen 1; Dendritic cell-specific protein CREA7-1
• Gene Name: JAML
• Related Disease:
  Atrial fibrillation
  Cardiac failure
  Congestive heart failure
  Kidney neoplasm
• UniProt ID: JAML_HUMAN
• Pfam ID: PF07686
• Sequence:
  MFCPLKLILLPVLLDYSLGLNDLNVSPPELTVHVGDSALMGCVFQSTEDKCIFKIDWTLS
  PGEHAKDEYVLYYYSNLSVPIGRFQNRVHLMGDILCNDGSLLLQDVQEADQGTYICEIRL
  KGESQVFKKAVVLHVLPEEPKELMVHVGGLIQMGCVFQSTEVKHVTKVEWIFSGRRAKEE
  IVFRYYHKLRMSVEYSQSWGHFQNRVNLVGDIFRNDGSIMLQGVRESDGGNYTCSIHLGN
  LVFKKTIVLHVSPEEPRTLVTPAALRPLVLGGNQLVIIVGIVCATILLLPVLILIVKKTC
  GNKSSVNSTVLVKNTKKTNPEIKEKPCHFERCEGEKHIYSPIIVREVIEEEEPSEKSEAT
  YMTMHPVWPSLRSDRNNSLEKKSGGGMPKTQQAF
• Function: Transmembrane protein of the plasma membrane of leukocytes that control their migration and activation through interaction with CXADR, a plasma membrane receptor found on adjacent epithelial and endothelial cells. The interaction between both receptors mediates the activation of gamma-delta T-cells, a subpopulation of T-cells residing in epithelia and involved in tissue homeostasis and repair. Upon epithelial CXADR-binding, JAML induces downstream cell signaling events in gamma-delta T-cells through PI3-kinase and MAP kinases. It results in proliferation and production of cytokines and growth factors by T-cells that in turn stimulate epithelial tissues repair. It also controls the transmigration of leukocytes within epithelial and endothelial tissues through adhesive interactions with epithelial and endothelial CXADR.
• Tissue Specificity: Expression is restricted to the hematopoietic tissues with the exception of liver. Expressed in fetal liver, spleen and thymus. Preferentially expressed by mature leukocytes (at protein level).
• Reactome Pathway:
  Cell surface interactions at the vascular wall (R-HSA-202733)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

4 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	[1]
Congestive heart failure	DIS32MEA	Strong	Biomarker	[1]
Kidney neoplasm	DISBNZTN	Strong	Biomarker	[2]

10 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 Junctional adhesion molecule-like (JAML).	[3]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Junctional adhesion molecule-like (JAML).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Junctional adhesion molecule-like (JAML).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Junctional adhesion molecule-like (JAML).	[6]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Junctional adhesion molecule-like (JAML).	[7]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Junctional adhesion molecule-like (JAML).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Junctional adhesion molecule-like (JAML).	[8]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Junctional adhesion molecule-like (JAML).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Junctional adhesion molecule-like (JAML).	[10]
QUERCITRIN	DM1DH96	Investigative	QUERCITRIN increases the expression of Junctional adhesion molecule-like (JAML).	[12]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Junctional adhesion molecule-like (JAML).	[11]

References

• [1] Catheter Ablation Versus Best Medical Therapy in Patients With Persistent Atrial Fibrillation and Congestive Heart Failure: The Randomized AMICA Trial.Circ Arrhythm Electrophysiol. 2019 Dec;12(12):e007731. doi: 10.1161/CIRCEP.119.007731. Epub 2019 Nov 25.
• [2] Chart for renal tumor microwave ablation from human study.Diagn Interv Imaging. 2018 Oct;99(10):609-614. doi: 10.1016/j.diii.2018.05.005. Epub 2018 Jun 15.
• [3] 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.
• [4] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [5] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [6] 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.
• [7] 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.
• [8] Benzo[a]pyrene-induced changes in microRNA-mRNA networks. Chem Res Toxicol. 2012 Apr 16;25(4):838-49.
• [9] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [10] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [11] 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.
• [12] Molecular mechanisms of quercitrin-induced apoptosis in non-small cell lung cancer. Arch Med Res. 2014 Aug;45(6):445-54.