Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTI3DJ7U)

• DOT Name: Integrin beta-6 (ITGB6)
• Gene Name: ITGB6
• Related Disease:
  Amelogenesis imperfecta type 1H
  Amelogenesis imperfecta type 1
  Amelogenesis imperfecta, type 3A
• UniProt ID: ITB6_HUMAN
• PDB ID: 4UM8; 4UM9; 5FFG; 5FFO; 5NEM; 5NER; 5NET; 5NEU; 8TCG
• Pfam ID: PF07974 ; PF18372 ; PF08725 ; PF07965 ; PF00362 ; PF17205
• Sequence:
  MGIELLCLFFLFLGRNDHVQGGCALGGAETCEDCLLIGPQCAWCAQENFTHPSGVGERCD
  TPANLLAKGCQLNFIENPVSQVEILKNKPLSVGRQKNSSDIVQIAPQSLILKLRPGGAQT
  LQVHVRQTEDYPVDLYYLMDLSASMDDDLNTIKELGSRLSKEMSKLTSNFRLGFGSFVEK
  PVSPFVKTTPEEIANPCSSIPYFCLPTFGFKHILPLTNDAERFNEIVKNQKISANIDTPE
  GGFDAIMQAAVCKEKIGWRNDSLHLLVFVSDADSHFGMDSKLAGIVIPNDGLCHLDSKNE
  YSMSTVLEYPTIGQLIDKLVQNNVLLIFAVTQEQVHLYENYAKLIPGATVGLLQKDSGNI
  LQLIISAYEELRSEVELEVLGDTEGLNLSFTAICNNGTLFQHQKKCSHMKVGDTASFSVT
  VNIPHCERRSRHIIIKPVGLGDALELLVSPECNCDCQKEVEVNSSKCHHGNGSFQCGVCA
  CHPGHMGPRCECGEDMLSTDSCKEAPDHPSCSGRGDCYCGQCICHLSPYGNIYGPYCQCD
  NFSCVRHKGLLCGGNGDCDCGECVCRSGWTGEYCNCTTSTDSCVSEDGVLCSGRGDCVCG
  KCVCTNPGASGPTCERCPTCGDPCNSKRSCIECHLSAAGQAREECVDKCKLAGATISEEE
  DFSKDGSVSCSLQGENECLITFLITTDNEGKTIIHSINEKDCPKPPNIPMIMLGVSLAIL
  LIGVVLLCIWKLLVSFHDRKEVAKFEAERSKAKWQTGTNPLYRGSTSTFKNVTYKHREKQ
  KVDLSTDC
• Function: Integrin alpha-V:beta-6 (ITGAV:ITGB6) is a receptor for fibronectin and cytotactin. It recognizes the sequence R-G-D in its ligands. Internalization of integrin alpha-V/beta-6 via clathrin-mediated endocytosis promotes carcinoma cell invasion. ITGAV:ITGB6 acts as a receptor for fibrillin-1 (FBN1) and mediates R-G-D-dependent cell adhesion to FBN1. Integrin alpha-V:beta-6 (ITGAV:ITGB6) mediates R-G-D-dependent release of transforming growth factor beta-1 (TGF-beta-1) from regulatory Latency-associated peptide (LAP), thereby playing a key role in TGF-beta-1 activation ; (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Coxsackievirus A9 and Coxsackievirus B1; (Microbial infection) Integrin ITGAV:ITGB6 acts as a receptor for Herpes simplex virus-1/HHV-1.
• KEGG Pathway:
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  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:
  Molecules associated with elastic fibres (R-HSA-2129379)
  Integrin cell surface interactions (R-HSA-216083)
  TGF-beta receptor signaling activates SMADs (R-HSA-2173789)
  ECM proteoglycans (R-HSA-3000178)
  Elastic fibre formation (R-HSA-1566948)

Molecular Interaction Atlas (MIA) of This DOT

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Amelogenesis imperfecta type 1H	DISYUYB7	Strong	Autosomal recessive	[1]
Amelogenesis imperfecta type 1	DISVEG5A	Supportive	Autosomal dominant	[2]
Amelogenesis imperfecta, type 3A	DISP3OJG	Supportive	Autosomal dominant	[3]

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 Integrin beta-6 (ITGB6).	[4]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Integrin beta-6 (ITGB6).	[16]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Integrin beta-6 (ITGB6).	[18]

17 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 Integrin beta-6 (ITGB6).	[5]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Integrin beta-6 (ITGB6).	[6]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Integrin beta-6 (ITGB6).	[7]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide decreases the expression of Integrin beta-6 (ITGB6).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Integrin beta-6 (ITGB6).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Integrin beta-6 (ITGB6).	[9]
Bortezomib	DMNO38U	Approved	Bortezomib increases the expression of Integrin beta-6 (ITGB6).	[10]
Paclitaxel	DMLB81S	Approved	Paclitaxel decreases the expression of Integrin beta-6 (ITGB6).	[11]
Permethrin	DMZ0Q1G	Approved	Permethrin decreases the expression of Integrin beta-6 (ITGB6).	[12]
Ethinyl estradiol	DMODJ40	Approved	Ethinyl estradiol affects the expression of Integrin beta-6 (ITGB6).	[13]
Cocaine	DMSOX7I	Approved	Cocaine increases the expression of Integrin beta-6 (ITGB6).	[14]
Bexarotene	DMOBIKY	Approved	Bexarotene increases the expression of Integrin beta-6 (ITGB6).	[15]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Integrin beta-6 (ITGB6).	[7]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Integrin beta-6 (ITGB6).	[17]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Integrin beta-6 (ITGB6).	[19]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Integrin beta-6 (ITGB6).	[20]
4-hydroxy-2-nonenal	DM2LJFZ	Investigative	4-hydroxy-2-nonenal decreases the expression of Integrin beta-6 (ITGB6).	[8]

References

• [1] Critical role for v6 integrin in enamel biomineralization. J Cell Sci. 2013 Feb 1;126(Pt 3):732-44. doi: 10.1242/jcs.112599. Epub 2012 Dec 21.
• [2] ITGB6 loss-of-function mutations cause autosomal recessive amelogenesis imperfecta. Hum Mol Genet. 2014 Apr 15;23(8):2157-63. doi: 10.1093/hmg/ddt611. Epub 2013 Dec 4.
• [3] A missense mutation in ITGB6 causes pitted hypomineralized amelogenesis imperfecta. Hum Mol Genet. 2014 Apr 15;23(8):2189-97. doi: 10.1093/hmg/ddt616. Epub 2013 Dec 6.
• [4] 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.
• [5] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [6] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [7] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [8] Microarray analysis of H2O2-, HNE-, or tBH-treated ARPE-19 cells. Free Radic Biol Med. 2002 Nov 15;33(10):1419-32.
• [9] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [10] The proapoptotic effect of zoledronic acid is independent of either the bone microenvironment or the intrinsic resistance to bortezomib of myeloma cells and is enhanced by the combination with arsenic trioxide. Exp Hematol. 2011 Jan;39(1):55-65.
• [11] Identification of selective inhibitors of cancer stem cells by high-throughput screening. Cell. 2009 Aug 21;138(4):645-659. doi: 10.1016/j.cell.2009.06.034. Epub 2009 Aug 13.
• [12] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [13] Dose- and time-dependent transcriptional response of Ishikawa cells exposed to genistein. Toxicol Sci. 2016 May;151(1):71-87.
• [14] Gene expression in human hippocampus from cocaine abusers identifies genes which regulate extracellular matrix remodeling. PLoS One. 2007 Nov 14;2(11):e1187. doi: 10.1371/journal.pone.0001187.
• [15] Identification of biomarkers modulated by the rexinoid LGD1069 (bexarotene) in human breast cells using oligonucleotide arrays. Cancer Res. 2006 Dec 15;66(24):12009-18.
• [16] 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.
• [17] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [18] 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.
• [19] 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.
• [20] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.