Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT43JEP1)

• DOT Name: Matrix remodeling-associated protein 8 (MXRA8)
• Synonyms: Limitrin
• Gene Name: MXRA8
• Related Disease:
  Chikungunya virus infection
  Hepatocellular carcinoma
• UniProt ID: MXRA8_HUMAN
• PDB ID: 6JO8
• Pfam ID: PF07686
• Sequence:
  MALPSRILLWKLVLLQSSAVLLHSGSSVPAAAGSSVVSESAVSWEAGARAVLRCQSPRMV
  WTQDRLHDRQRVLHWDLRGPGGGPARRLLDLYSAGEQRVYEARDRGRLELSASAFDDGNF
  SLLIRAVEETDAGLYTCNLHHHYCHLYESLAVRLEVTDGPPATPAYWDGEKEVLAVARGA
  PALLTCVNRGHVWTDRHVEEAQQVVHWDRQPPGVPHDRADRLLDLYASGERRAYGPLFLR
  DRVAVGADAFERGDFSLRIEPLEVADEGTYSCHLHHHYCGLHERRVFHLTVAEPHAEPPP
  RGSPGNGSSHSGAPGPDPTLARGHNVINVIVPESRAHFFQQLGYVLATLLLFILLLVTVL
  LAARRRRGGYEYSDQKSGKSKGKDVNLAEFAVAAGDQMLYRSEDIQLDYKNNILKERAEL
  AHSPLPAKYIDLDKGFRKENCK
• Function: Transmembrane protein which can modulate activity of various signaling pathways, probably via binding to integrin ITGAV:ITGB3. Mediates heterophilic cell-cell interactions in vitro. Inhibits osteoclastogenesis downstream of TNFSF11/RANKL and CSF1, where it may function by attenuating signaling via integrin ITGB3 and MAP kinase p38. Plays a role in cartilage formation where it promotes proliferation and maturation of growth plate chondrocytes. Stimulates formation of primary cilia in chondrocytes. Enhances expression of genes involved in the hedgehog signaling pathway in chondrocytes, including the hedgehog signaling molecule IHH; may also promote signaling via the PTHLH/PTHrP pathway. Plays a role in angiogenesis where it suppresses migration of endothelial cells and also promotes their apoptosis. Inhibits VEGF-induced activation of AKT and p38 MAP kinase in endothelial cells. Also inhibits VTN (vitronectin)-mediated integrin ITGAV:ITGB3 signaling and activation of PTK2/FAK. May play a role in the maturation and maintenance of the blood-brain barrier; (Microbial infection) Contributes to arthritogenic alphavirus pathogenesis and acts as a receptor for these viruses.
• Tissue Specificity: Detected in endothelial cells in mammary tissue, in both large vessels (left internal mammary artery) and small capillaries (vasa vasorum of the adventitia).
• Reactome Pathway:
  Post-translational protein phosphorylation (R-HSA-8957275)
  Regulation of Insulin-like Growth Factor (IGF) transport and uptake by Insulin-like Growth Factor Binding Proteins (IGFBPs) (R-HSA-381426)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[1]
Hepatocellular carcinoma	DIS0J828	Strong	Biomarker	[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 Matrix remodeling-associated protein 8 (MXRA8).	[3]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Matrix remodeling-associated protein 8 (MXRA8).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Matrix remodeling-associated protein 8 (MXRA8).	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[4]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[5]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[6]
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[7]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[8]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[9]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[10]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[11]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[13]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of Matrix remodeling-associated protein 8 (MXRA8).	[15]

References

• [1] Structures Unveil the Invasion Mechanism of Chikungunya Virus.Trends Microbiol. 2019 Aug;27(8):656-658. doi: 10.1016/j.tim.2019.05.011. Epub 2019 Jun 17.
• [2] Identification and Characterization of a Novel Protein ASP-3 Purified from Arca subcrenata and Its Antitumor Mechanism.Mar Drugs. 2019 Sep 9;17(9):528. doi: 10.3390/md17090528.
• [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] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [6] Predictive toxicology using systemic biology and liver microfluidic "on chip" approaches: application to acetaminophen injury. Toxicol Appl Pharmacol. 2012 Mar 15;259(3):270-80.
• [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.
• [8] Identification of vitamin D3 target genes in human breast cancer tissue. J Steroid Biochem Mol Biol. 2016 Nov;164:90-97.
• [9] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [10] Folic acid induces cell type-specific changes in the transcriptome of breast cancer cell lines: a proof-of-concept study. J Nutr Sci. 2016 Apr 26;5:e17. doi: 10.1017/jns.2016.8. eCollection 2016.
• [11] 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.
• [12] 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.
• [13] 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.
• [14] 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.
• [15] Cellular reactions to long-term volatile organic compound (VOC) exposures. Sci Rep. 2016 Dec 1;6:37842. doi: 10.1038/srep37842.