Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3FA39C)

• DOT Name: Integrin alpha-6 (ITGA6)
• Synonyms: CD49 antigen-like family member F; VLA-6; CD antigen CD49f
• Gene Name: ITGA6
• Related Disease: Junctional epidermolysis bullosa with pyloric atresia
• UniProt ID: ITA6_HUMAN
• PDB ID: 7CEB; 7CEC
• Pfam ID: PF01839 ; PF08441 ; PF20805 ; PF20806
• Sequence:
  MAAAGQLCLLYLSAGLLSRLGAAFNLDTREDNVIRKYGDPGSLFGFSLAMHWQLQPEDKR
  LLLVGAPRAEALPLQRANRTGGLYSCDITARGPCTRIEFDNDADPTSESKEDQWMGVTVQ
  SQGPGGKVVTCAHRYEKRQHVNTKQESRDIFGRCYVLSQNLRIEDDMDGGDWSFCDGRLR
  GHEKFGSCQQGVAATFTKDFHYIVFGAPGTYNWKGIVRVEQKNNTFFDMNIFEDGPYEVG
  GETEHDESLVPVPANSYLGLLFLTSVSYTDPDQFVYKTRPPREQPDTFPDVMMNSYLGFS
  LDSGKGIVSKDEITFVSGAPRANHSGAVVLLKRDMKSAHLLPEHIFDGEGLASSFGYDVA
  VVDLNKDGWQDIVIGAPQYFDRDGEVGGAVYVYMNQQGRWNNVKPIRLNGTKDSMFGIAV
  KNIGDINQDGYPDIAVGAPYDDLGKVFIYHGSANGINTKPTQVLKGISPYFGYSIAGNMD
  LDRNSYPDVAVGSLSDSVTIFRSRPVINIQKTITVTPNRIDLRQKTACGAPSGICLQVKS
  CFEYTANPAGYNPSISIVGTLEAEKERRKSGLSSRVQFRNQGSEPKYTQELTLKRQKQKV
  CMEETLWLQDNIRDKLRPIPITASVEIQEPSSRRRVNSLPEVLPILNSDEPKTAHIDVHF
  LKEGCGDDNVCNSNLKLEYKFCTREGNQDKFSYLPIQKGVPELVLKDQKDIALEITVTNS
  PSNPRNPTKDGDDAHEAKLIATFPDTLTYSAYRELRAFPEKQLSCVANQNGSQADCELGN
  PFKRNSNVTFYLVLSTTEVTFDTPDLDINLKLETTSNQDNLAPITAKAKVVIELLLSVSG
  VAKPSQVYFGGTVVGEQAMKSEDEVGSLIEYEFRVINLGKPLTNLGTATLNIQWPKEISN
  GKWLLYLVKVESKGLEKVTCEPQKEINSLNLTESHNSRKKREITEKQIDDNRKFSLFAER
  KYQTLNCSVNVNCVNIRCPLRGLDSKASLILRSRLWNSTFLEEYSKLNYLDILMRAFIDV
  TAAAENIRLPNAGTQVRVTVFPSKTVAQYSGVPWWIILVAILAGILMLALLVFILWKCGF
  FKRSRYDDSVPRYHAVRIRKEEREIKDEKYIDNLEKKQWITKWNENESYS
• Function: Integrin alpha-6/beta-1 (ITGA6:ITGB1) is a receptor for laminin on platelets. Integrin alpha-6/beta-1 (ITGA6:ITGB1) is present in oocytes and is involved in sperm-egg fusion. Integrin alpha-6/beta-4 (ITGA6:ITGB4) is a receptor for laminin in epithelial cells and it plays a critical structural role in the hemidesmosome. ITGA6:ITGB4 binds to NRG1 (via EGF domain) and this binding is essential for NRG1-ERBB signaling. ITGA6:ITGB4 binds to IGF1 and this binding is essential for IGF1 signaling. ITGA6:ITGB4 binds to IGF2 and this binding is essential for IGF2 signaling.
• Tissue Specificity: Integrin alpha-6/beta-4 is predominantly expressed by epithelia. Isoforms containing segment X1 are ubiquitously expressed. Isoforms containing segment X1X2 are expressed in heart, kidney, placenta, colon, duodenum, myoblasts and myotubes, and in a limited number of cell lines; they are always coexpressed with the ubiquitous isoform containing segment X1. In some tissues (e.g. Salivary gland), isoforms containing cytoplasmic segment A and isoforms containing segment B are detected while in others, only isoforms containing one cytoplasmic segment are found (segment A in epidermis and segment B in kidney). Processed integrin alpha-6: Expressed at low levels in normal prostate tissue with elevated levels in prostate cancer tissue (at protein level) .
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Cell adhesion molecules (hsa04514)
  Hematopoietic cell lineage (hsa04640)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  Toxoplasmosis (hsa05145)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Small cell lung cancer (hsa05222)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Basigin interactions (R-HSA-210991)
  Integrin cell surface interactions (R-HSA-216083)
  Laminin interactions (R-HSA-3000157)
  Syndecan interactions (R-HSA-3000170)
  Type I hemidesmosome assembly (R-HSA-446107)
  Assembly of collagen fibrils and other multimeric structures (R-HSA-2022090)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Junctional epidermolysis bullosa with pyloric atresia	DIS5QMS0	Strong	Autosomal recessive	[1]

29 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-6 (ITGA6).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Integrin alpha-6 (ITGA6).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Integrin alpha-6 (ITGA6).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Integrin alpha-6 (ITGA6).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrin alpha-6 (ITGA6).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Integrin alpha-6 (ITGA6).	[7]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Integrin alpha-6 (ITGA6).	[8]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Integrin alpha-6 (ITGA6).	[9]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integrin alpha-6 (ITGA6).	[10]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Integrin alpha-6 (ITGA6).	[11]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Integrin alpha-6 (ITGA6).	[12]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Integrin alpha-6 (ITGA6).	[13]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Integrin alpha-6 (ITGA6).	[14]
Folic acid	DMEMBJC	Approved	Folic acid affects the expression of Integrin alpha-6 (ITGA6).	[15]
Bortezomib	DMNO38U	Approved	Bortezomib decreases the expression of Integrin alpha-6 (ITGA6).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib decreases the expression of Integrin alpha-6 (ITGA6).	[17]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Integrin alpha-6 (ITGA6).	[18]
Mifepristone	DMGZQEF	Approved	Mifepristone increases the expression of Integrin alpha-6 (ITGA6).	[19]
Diazepam	DM08E9O	Approved	Diazepam decreases the expression of Integrin alpha-6 (ITGA6).	[20]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Integrin alpha-6 (ITGA6).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Integrin alpha-6 (ITGA6).	[22]
Eugenol	DM7US1H	Patented	Eugenol increases the expression of Integrin alpha-6 (ITGA6).	[23]
SB-431542	DM0YOXQ	Preclinical	SB-431542 increases the expression of Integrin alpha-6 (ITGA6).	[24]
Scriptaid	DM9JZ21	Preclinical	Scriptaid affects the expression of Integrin alpha-6 (ITGA6).	[25]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Integrin alpha-6 (ITGA6).	[26]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Integrin alpha-6 (ITGA6).	[27]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Integrin alpha-6 (ITGA6).	[28]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Integrin alpha-6 (ITGA6).	[29]
Arachidonic acid	DMUOQZD	Investigative	Arachidonic acid increases the expression of Integrin alpha-6 (ITGA6).	[30]

References

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• [18] Cannabidiol Displays Proteomic Similarities to Antipsychotics in Cuprizone-Exposed Human Oligodendrocytic Cell Line MO3.13. Front Mol Neurosci. 2021 May 28;14:673144. doi: 10.3389/fnmol.2021.673144. eCollection 2021.
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• [21] Suppression of cancer relapse and metastasis by inhibiting cancer stemness. Proc Natl Acad Sci U S A. 2015 Feb 10;112(6):1839-44. doi: 10.1073/pnas.1424171112. Epub 2015 Jan 20.
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• [23] Chemicals with weak skin sensitizing properties can be identified using low-density microarrays on immature dendritic cells. Toxicol Lett. 2007 Nov 1;174(1-3):98-109. doi: 10.1016/j.toxlet.2007.08.015. Epub 2007 Sep 5.
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• [25] Histone deacetylase inhibitor scriptaid induces cell cycle arrest and epigenetic change in colon cancer cells. Int J Oncol. 2008 Oct;33(4):767-76.
• [26] Bisphenolic compounds alter gene expression in MCF-7 cells through interaction with estrogen receptor . Toxicol Appl Pharmacol. 2020 Jul 15;399:115030. doi: 10.1016/j.taap.2020.115030. Epub 2020 May 6.
• [27] 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.
• [28] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.
• [29] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [30] Arachidonic acid-induced gene expression in colon cancer cells. Carcinogenesis. 2006 Oct;27(10):1950-60.