Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTBH8WFD)

• DOT Name: Integrin alpha-8 (ITGA8)
• Gene Name: ITGA8
• Related Disease:
  Renal hypodysplasia/aplasia 1
  Bilateral renal agenesis
• UniProt ID: ITA8_HUMAN
• Pfam ID: PF01839 ; PF08441 ; PF20805 ; PF20806 ; PF00357
• Sequence:
  MSPGASRGPRGSQAPLIAPLCCAAAALGMLLWSPACQAFNLDVEKLTVYSGPKGSYFGYA
  VDFHIPDARTASVLVGAPKANTSQPDIVEGGAVYYCPWPAEGSAQCRQIPFDTTNNRKIR
  VNGTKEPIEFKSNQWFGATVKAHKGKVVACAPLYHWRTLKPTPEKDPVGTCYVAIQNFSA
  YAEFSPCRNSNADPEGQGYCQAGFSLDFYKNGDLIVGGPGSFYWQGQVITASVADIIANY
  SFKDILRKLAGEKQTEVAPASYDDSYLGYSVAAGEFTGDSQQELVAGIPRGAQNFGYVSI
  INSTDMTFIQNFTGEQMASYFGYTVVVSDVNSDGLDDVLVGAPLFMEREFESNPREVGQI
  YLYLQVSSLLFRDPQILTGTETFGRFGSAMAHLGDLNQDGYNDIAIGVPFAGKDQRGKVL
  IYNGNKDGLNTKPSQVLQGVWASHAVPSGFGFTLRGDSDIDKNDYPDLIVGAFGTGKVAV
  YRARPVVTVDAQLLLHPMIINLENKTCQVPDSMTSAACFSLRVCASVTGQSIANTIVLMA
  EVQLDSLKQKGAIKRTLFLDNHQAHRVFPLVIKRQKSHQCQDFIVYLRDETEFRDKLSPI
  NISLNYSLDESTFKEGLEVKPILNYYRENIVSEQAHILVDCGEDNLCVPDLKLSARPDKH
  QVIIGDENHLMLIINARNEGEGAYEAELFVMIPEEADYVGIERNNKGFRPLSCEYKMENV
  TRMVVCDLGNPMVSGTNYSLGLRFAVPRLEKTNMSINFDLQIRSSNKDNPDSNFVSLQIN
  ITAVAQVEIRGVSHPPQIVLPIHNWEPEEEPHKEEEVGPLVEHIYELHNIGPSTISDTIL
  EVGWPFSARDEFLLYIFHIQTLGPLQCQPNPNINPQDIKPAASPEDTPELSAFLRNSTIP
  HLVRKRDVHVVEFHRQSPAKILNCTNIECLQISCAVGRLEGGESAVLKVRSRLWAHTFLQ
  RKNDPYALASLVSFEVKKMPYTDQPAKLPEGSIVIKTSVIWATPNVSFSIPLWVIILAIL
  LGLLVLAILTLALWKCGFFDRARPPQEDMTDREQLTNDKTPEA
• Function: Integrin alpha-8/beta-1 functions in the genesis of kidney and probably of other organs by regulating the recruitment of mesenchymal cells into epithelial structures. It recognizes the sequence R-G-D in a wide array of ligands including TNC, FN1, SPP1 TGFB1, TGFB3 and VTN. NPNT is probably its functional ligand in kidney genesis. Neuronal receptor for TNC it mediates cell-cell interactions and regulates neurite outgrowth of sensory and motor neurons.
• Tissue Specificity: Expressed in mesenchymal cells, including alveolar myofibroblasts, kidney mesangial cells and hepatic stellar cells and vascular and visceral smooth muscle (at protein level).
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cell adhesion molecules (hsa04514)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  Human papillomavirus infection (hsa05165)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Integrin cell surface interactions (R-HSA-216083)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  ECM proteoglycans (R-HSA-3000178)
  Molecules associated with elastic fibres (R-HSA-2129379)

Molecular Interaction Atlas (MIA) of This DOT

2 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Renal hypodysplasia/aplasia 1	DISOH8XN	Strong	Autosomal recessive	[1]
Bilateral renal agenesis	DISOR5IA	Supportive	Autosomal recessive	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Integrin alpha-8 (ITGA8).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Integrin alpha-8 (ITGA8).	[4]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Integrin alpha-8 (ITGA8).	[6]
Panobinostat	DM58WKG	Approved	Panobinostat increases the expression of Integrin alpha-8 (ITGA8).	[6]
Phenytoin	DMNOKBV	Approved	Phenytoin increases the expression of Integrin alpha-8 (ITGA8).	[7]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Integrin alpha-8 (ITGA8).	[9]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Integrin alpha-8 (ITGA8).	[10]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Integrin alpha-8 (ITGA8).	[5]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Integrin alpha-8 (ITGA8).	[8]

References

• [1] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [2] Integrin alpha 8 recessive mutations are responsible for bilateral renal agenesis in humans. Am J Hum Genet. 2014 Feb 6;94(2):288-94. doi: 10.1016/j.ajhg.2013.12.017. Epub 2014 Jan 16.
• [3] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [4] Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
• [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] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [7] Role of phenytoin in wound healing: microarray analysis of early transcriptional responses in human dermal fibroblasts. Biochem Biophys Res Commun. 2004 Feb 13;314(3):661-6. doi: 10.1016/j.bbrc.2003.12.146.
• [8] 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.
• [9] Bisphenol A and bisphenol S induce distinct transcriptional profiles in differentiating human primary preadipocytes. PLoS One. 2016 Sep 29;11(9):e0163318.
• [10] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.