Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTPFL017)

• DOT Name: Integrin alpha-2 (ITGA2)
• Synonyms: CD49 antigen-like family member B; Collagen receptor; Platelet membrane glycoprotein Ia; GPIa; VLA-2 subunit alpha; CD antigen CD49b
• Gene Name: ITGA2
• Related Disease: Platelet-type bleeding disorder 9
• UniProt ID: ITA2_HUMAN
• PDB ID: 1AOX; 1DZI; 1V7P; 4BJ3; 5HJ2; 5THP; 6ND8; 6ND9; 6NDA; 6NDB; 6NDC; 6NDD; 6NDE; 6NDF; 6NDG; 6NDH
• Pfam ID: PF01839 ; PF20805 ; PF20806 ; PF00092
• Sequence:
  MGPERTGAAPLPLLLVLALSQGILNCCLAYNVGLPEAKIFSGPSSEQFGYAVQQFINPKG
  NWLLVGSPWSGFPENRMGDVYKCPVDLSTATCEKLNLQTSTSIPNVTEMKTNMSLGLILT
  RNMGTGGFLTCGPLWAQQCGNQYYTTGVCSDISPDFQLSASFSPATQPCPSLIDVVVVCD
  ESNSIYPWDAVKNFLEKFVQGLDIGPTKTQVGLIQYANNPRVVFNLNTYKTKEEMIVATS
  QTSQYGGDLTNTFGAIQYARKYAYSAASGGRRSATKVMVVVTDGESHDGSMLKAVIDQCN
  HDNILRFGIAVLGYLNRNALDTKNLIKEIKAIASIPTERYFFNVSDEAALLEKAGTLGEQ
  IFSIEGTVQGGDNFQMEMSQVGFSADYSSQNDILMLGAVGAFGWSGTIVQKTSHGHLIFP
  KQAFDQILQDRNHSSYLGYSVAAISTGESTHFVAGAPRANYTGQIVLYSVNENGNITVIQ
  AHRGDQIGSYFGSVLCSVDVDKDTITDVLLVGAPMYMSDLKKEEGRVYLFTIKEGILGQH
  QFLEGPEGIENTRFGSAIAALSDINMDGFNDVIVGSPLENQNSGAVYIYNGHQGTIRTKY
  SQKILGSDGAFRSHLQYFGRSLDGYGDLNGDSITDVSIGAFGQVVQLWSQSIADVAIEAS
  FTPEKITLVNKNAQIILKLCFSAKFRPTKQNNQVAIVYNITLDADGFSSRVTSRGLFKEN
  NERCLQKNMVVNQAQSCPEHIIYIQEPSDVVNSLDLRVDISLENPGTSPALEAYSETAKV
  FSIPFHKDCGEDGLCISDLVLDVRQIPAAQEQPFIVSNQNKRLTFSVTLKNKRESAYNTG
  IVVDFSENLFFASFSLPVDGTEVTCQVAASQKSVACDVGYPALKREQQVTFTINFDFNLQ
  NLQNQASLSFQALSESQEENKADNLVNLKIPLLYDAEIHLTRSTNINFYEISSDGNVPSI
  VHSFEDVGPKFIFSLKVTTGSVPVSMATVIIHIPQYTKEKNPLMYLTGVQTDKAGDISCN
  ADINPLKIGQTSSSVSFKSENFRHTKELNCRTASCSNVTCWLKDVHMKGEYFVNVTTRIW
  NGTFASSTFQTVQLTAAAEINTYNPEIYVIEDNTVTIPLMIMKPDEKAEVPTGVIIGSII
  AGILLLLALVAILWKLGFFKRKYEKMTKNPDEIDETTELSS
• Function: Integrin alpha-2/beta-1 is a receptor for laminin, collagen, collagen C-propeptides, fibronectin and E-cadherin. It recognizes the proline-hydroxylated sequence G-F-P-G-E-R in collagen. It is responsible for adhesion of platelets and other cells to collagens, modulation of collagen and collagenase gene expression, force generation and organization of newly synthesized extracellular matrix.; (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human rotavirus A; (Microbial infection) Integrin ITGA2:ITGB1 acts as a receptor for Human echoviruses 1 and 8.
• KEGG Pathway:
  Virion - Rotavirus (hsa03271)
  Phagosome (hsa04145)
  PI3K-Akt sig.ling pathway (hsa04151)
  Focal adhesion (hsa04510)
  ECM-receptor interaction (hsa04512)
  Platelet activation (hsa04611)
  Hematopoietic cell lineage (hsa04640)
  Regulation of actin cytoskeleton (hsa04810)
  Cytoskeleton in muscle cells (hsa04820)
  Human papillomavirus infection (hsa05165)
  Pathways in cancer (hsa05200)
  Proteoglycans in cancer (hsa05205)
  Small cell lung cancer (hsa05222)
  Hypertrophic cardiomyopathy (hsa05410)
  Arrhythmogenic right ventricular cardiomyopathy (hsa05412)
  Dilated cardiomyopathy (hsa05414)
• Reactome Pathway:
  Laminin interactions (R-HSA-3000157)
  Syndecan interactions (R-HSA-3000170)
  ECM proteoglycans (R-HSA-3000178)
  CHL1 interactions (R-HSA-447041)
  Platelet Adhesion to exposed collagen (R-HSA-75892)
  MET activates PTK2 signaling (R-HSA-8874081)
  Integrin cell surface interactions (R-HSA-216083)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Platelet-type bleeding disorder 9	DISFGCJT	Strong	Autosomal dominant	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Integrin alpha-2 (ITGA2) decreases the response to substance of Aspirin.	[34]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Integrin alpha-2 (ITGA2).	[2]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Integrin alpha-2 (ITGA2).	[29]

34 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 alpha-2 (ITGA2).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Integrin alpha-2 (ITGA2).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Integrin alpha-2 (ITGA2).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Integrin alpha-2 (ITGA2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Integrin alpha-2 (ITGA2).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Integrin alpha-2 (ITGA2).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Integrin alpha-2 (ITGA2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Integrin alpha-2 (ITGA2).	[10]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Integrin alpha-2 (ITGA2).	[11]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide increases the expression of Integrin alpha-2 (ITGA2).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Integrin alpha-2 (ITGA2).	[13]
Vorinostat	DMWMPD4	Approved	Vorinostat increases the expression of Integrin alpha-2 (ITGA2).	[14]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Integrin alpha-2 (ITGA2).	[13]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Integrin alpha-2 (ITGA2).	[15]
Troglitazone	DM3VFPD	Approved	Troglitazone increases the expression of Integrin alpha-2 (ITGA2).	[16]
Irinotecan	DMP6SC2	Approved	Irinotecan increases the expression of Integrin alpha-2 (ITGA2).	[17]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Integrin alpha-2 (ITGA2).	[15]
Sulindac	DM2QHZU	Approved	Sulindac increases the expression of Integrin alpha-2 (ITGA2).	[18]
Phenytoin	DMNOKBV	Approved	Phenytoin decreases the expression of Integrin alpha-2 (ITGA2).	[19]
Urethane	DM7NSI0	Phase 4	Urethane increases the expression of Integrin alpha-2 (ITGA2).	[20]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of Integrin alpha-2 (ITGA2).	[21]
Napabucasin	DMDZ6Q3	Phase 3	Napabucasin decreases the expression of Integrin alpha-2 (ITGA2).	[22]
Fenfluramine	DM0762O	Phase 3	Fenfluramine increases the expression of Integrin alpha-2 (ITGA2).	[23]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Integrin alpha-2 (ITGA2).	[24]
Belinostat	DM6OC53	Phase 2	Belinostat increases the expression of Integrin alpha-2 (ITGA2).	[14]
phorbol 12-myristate 13-acetate	DMJWD62	Phase 2	phorbol 12-myristate 13-acetate increases the expression of Integrin alpha-2 (ITGA2).	[25]
PD-0325901	DM27D4J	Phase 2	PD-0325901 decreases the expression of Integrin alpha-2 (ITGA2).	[26]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Integrin alpha-2 (ITGA2).	[10]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Integrin alpha-2 (ITGA2).	[27]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Integrin alpha-2 (ITGA2).	[28]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Integrin alpha-2 (ITGA2).	[30]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Integrin alpha-2 (ITGA2).	[31]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Integrin alpha-2 (ITGA2).	[32]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Integrin alpha-2 (ITGA2).	[33]

References

• [1] The new platelet alloantigen Cab a: a single point mutation Gln 716 His on the alpha 2 integrin. Transfusion. 2009 Oct;49(10):2076-83. doi: 10.1111/j.1537-2995.2009.02240.x. Epub 2009 Jun 4.
• [2] 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.
• [3] Altered oxidative status and integrin expression in cyclosporine A-treated oral epithelial cells. Toxicol Mech Methods. 2015 Feb;25(2):98-104. doi: 10.3109/15376516.2014.990595. Epub 2015 Jan 22.
• [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] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [6] 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.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [9] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [10] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [11] Endoplasmic reticulum stress contributes to arsenic trioxide-induced intrinsic apoptosis in human umbilical and bone marrow mesenchymal stem cells. Environ Toxicol. 2016 Mar;31(3):314-28.
• [12] Unique signatures of stress-induced senescent human astrocytes. Exp Neurol. 2020 Dec;334:113466. doi: 10.1016/j.expneurol.2020.113466. Epub 2020 Sep 17.
• [13] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [14] 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.
• [15] Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
• [16] Effects of ciglitazone and troglitazone on the proliferation of human stomach cancer cells. World J Gastroenterol. 2009 Jan 21;15(3):310-20.
• [17] Clinical determinants of response to irinotecan-based therapy derived from cell line models. Clin Cancer Res. 2008 Oct 15;14(20):6647-55.
• [18] Expression profile analysis of colon cancer cells in response to sulindac or aspirin. Biochem Biophys Res Commun. 2002 Mar 29;292(2):498-512.
• [19] Impaired degradation of matrix collagen in human gingival fibroblasts by the antiepileptic drug phenytoin. J Periodontol. 2005 Jun;76(6):941-50. doi: 10.1902/jop.2005.76.6.941.
• [20] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [21] Molecular mechanisms of resveratrol action in lung cancer cells using dual protein and microarray analyses. Cancer Res. 2007 Dec 15;67(24):12007-17. doi: 10.1158/0008-5472.CAN-07-2464.
• [22] 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.
• [23] Fenfluramine-induced gene dysregulation in human pulmonary artery smooth muscle and endothelial cells. Pulm Circ. 2011 Jul-Sep;1(3):405-18. doi: 10.4103/2045-8932.87310.
• [24] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [25] Transcriptional and epigenetic regulation of the integrin collagen receptor locus ITGA1-PELO-ITGA2. Biochim Biophys Acta. 2007 Sep-Oct;1769(9-10):546-58. doi: 10.1016/j.bbaexp.2007.06.004. Epub 2007 Jul 6.
• [26] PRC2 loss amplifies Ras-driven transcription and confers sensitivity to BRD4-based therapies. Nature. 2014 Oct 9;514(7521):247-51.
• [27] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [28] 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.
• [29] 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.
• [30] 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.
• [31] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [32] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.
• [33] 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.
• [34] Association of the platelet membrane glycoprotein I a C807T gene polymorphism with aspirin resistance. J Huazhong Univ Sci Technolog Med Sci. 2007 Dec;27(6):664-7. doi: 10.1007/s11596-007-0611-2.