Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTQ94R5K)

• DOT Name: Unconventional myosin-IXb (MYO9B)
• Synonyms: Unconventional myosin-9b
• Gene Name: MYO9B
• Related Disease:
  Dermatitis herpetiformis
  Abdominal aortic aneurysm
  Bacillary dysentery
  Barrett esophagus
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Crohn disease
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Familial prostate carcinoma
  High blood pressure
  Peptic esophagitis
  Prostate cancer, hereditary, 1
  Prostate carcinoma
  Rheumatoid arthritis
  Skin and skin-structure infection
  Systemic lupus erythematosus
  Turner syndrome
  Ulcerative colitis
  Advanced cancer
  Coronary heart disease
  Lung cancer
  Lung carcinoma
  Lung neoplasm
  Autoimmune disease
  Type-1 diabetes
• UniProt ID: MYO9B_HUMAN
• PDB ID: 5C5S; 5HPY
• Pfam ID: PF00612 ; PF00063 ; PF00788 ; PF00620
• Sequence:
  MSVKEAGSSGRREQAAYHLHIYPQLSTTESQASCRVTATKDSTTSDVIKDAIASLRLDGT
  KCYVLVEVKESGGEEWVLDANDSPVHRVLLWPRRAQDEHPQEDGYYFLLQERNADGTIKY
  VHMQLVAQATATRRLVERGLLPRQQADFDDLCNLPELTEGNLLKNLKHRFLQQKIYTYAG
  SILVAINPFKFLPIYNPKYVKMYENQQLGKLEPHVFALADVAYYTMLRKRVNQCIVISGE
  SGSGKTQSTNFLIHCLTALSQKGYASGVERTILGAGPVLEAFGNAKTAHNNNSSRFGKFI
  QVSYLESGIVRGAVVEKYLLEKSRLVSQEKDERNYHVFYYLLLGVSEEERQEFQLKQPED
  YFYLNQHNLKIEDGEDLKHDFERLKQAMEMVGFLPATKKQIFAVLSAILYLGNVTYKKRA
  TGREEGLEVGPPEVLDTLSQLLKVKREILVEVLTKRKTVTVNDKLILPYSLSEAITARDS
  MAKSLYSALFDWIVLRINHALLNKKDVEEAVSCLSIGVLDIFGFEDFERNSFEQFCINYA
  NEQLQYYFNQHIFKLEQEEYQGEGITWHNIGYTDNVGCIHLISKKPTGLFYLLDEESNFP
  HATSQTLLAKFKQQHEDNKYFLGTPVMEPAFIIQHFAGKVKYQIKDFREKNMDYMRPDIV
  ALLRGSDSSYVRELIGMDPVAVFRWAVLRAAIRAMAVLREAGRLRAERAEKAAGMSSPGA
  QSHPEELPRGASTPSEKLYRDLHNQMIKSIKGLPWQGEDPRSLLQSLSRLQKPRAFILKS
  KGIKQKQIIPKNLLDSKSLKLIISMTLHDRTTKSLLHLHKKKKPPSISAQFQTSLNKLLE
  ALGKAEPFFIRCIRSNAEKKELCFDDELVLQQLRYTGMLETVRIRRSGYSAKYTFQDFTE
  QFQVLLPKDAQPCREVISTLLEKMKIDKRNYQIGKTKVFLKETERQALQETLHREVVRKI
  LLLQSWFRMVLERRHFLQMKRAAVTIQACWRSYRVRRALERTQAAVYLQASWRGYWQRKL
  YRHQKQSIIRLQSLCRGHLQRKSFSQMISEKQKAEEKEREALEAARAGAEEGGQGQAAGG
  QQVAEQGPEPAEDGGHLASEPEVQPSDRSPLEHSSPEKEAPSPEKTLPPQKTVAAESHEK
  VPSSREKRESRRQRGLEHVKFQNKHIQSCKEESALREPSRRVTQEQGVSLLEDKKESRED
  ETLLVVETEAENTSQKQPTEQPQAMAVGKVSEETEKTLPSGSPRPGQLERPTSLALDSRV
  SPPAPGSAPETPEDKSKPCGSPRVQEKPDSPGGSTQIQRYLDAERLASAVELWRGKKLVA
  AASPSAMLSQSLDLSDRHRATGAALTPTEERRTSFSTSDVSKLLPSLAKAQPAAETTDGE
  RSAKKPAVQKKKPGDASSLPDAGLSPGSQVDSKSTFKRLFLHKTKDKKYSLEGAEELENA
  VSGHVVLEATTMKKGLEAPSGQQHRHAAGEKRTKEPGGKGKKNRNVKIGKITVSEKWRES
  VFRQITNANELKYLDEFLLNKINDLRSQKTPIESLFIEATEKFRSNIKTMYSVPNGKIHV
  GYKDLMENYQIVVSNLATERGQKDTNLVLNLFQSLLDEFTRGYTKNDFEPVKQSKAQKKK
  RKQERAVQEHNGHVFASYQVSIPQSCEQCLSYIWLMDKALLCSVCKMTCHKKCVHKIQSH
  CSYTYGRKGEPGVEPGHFGVCVDSLTSDKASVPIVLEKLLEHVEMHGLYTEGLYRKSGAA
  NRTRELRQALQTDPAAVKLENFPIHAITGVLKQWLRELPEPLMTFAQYGDFLRAVELPEK
  QEQLAAIYAVLEHLPEANHNSLERLIFHLVKVALLEDVNRMSPGALAIIFAPCLLRCPDN
  SDPLTSMKDVLKITTCVEMLIKEQMRKYKVKMEEISQLEAAESIAFRRLSLLRQNAPWPL
  KLGFSSPYEGVLNKSPKTRDIQEEELEVLLEEEAAGGDEDREKEILIERIQSIKEEKEDI
  TYRLPELDPRGSDEENLDSETSASTESLLEERAGRGASEGPPAPALPCPGAPTPSPLPTV
  AAPPRRRPSSFVTVRVKTPRRTPIMPTANIKLPPGLPSHLPRWAPGAREAAAPVRRREPP
  ARRPDQIHSVYITPGADLPVQGALEPLEEDGQPPGAKRRYSDPPTYCLPPASGQTNG
• Function: Myosins are actin-based motor molecules with ATPase activity. Unconventional myosins serve in intracellular movements. Binds actin with high affinity both in the absence and presence of ATP and its mechanochemical activity is inhibited by calcium ions. Also acts as a GTPase activator for RHOA. Plays a role in the regulation of cell migration via its role as RHOA GTPase activator. This is regulated by its interaction with the SLIT2 receptor ROBO1; interaction with ROBO1 impairs interaction with RHOA and subsequent activation of RHOA GTPase activity, and thereby leads to increased levels of active, GTP-bound RHOA.
• Tissue Specificity: Detected in peripheral blood leukocytes (at protein level) . Expressed predominantly in peripheral blood leukocytes and at lower levels, in thymus, spleen, testis, prostate, ovary, brain, small intestine and lung.
• KEGG Pathway: Motor proteins (hsa04814)
• Reactome Pathway:
  RHOA GTPase cycle (R-HSA-8980692)
  SLIT2 (R-HSA-8985586)
  RHOB GTPase cycle (R-HSA-9013026)
  RHOC GTPase cycle (R-HSA-9013106)
  CDC42 GTPase cycle (R-HSA-9013148)
  RAC1 GTPase cycle (R-HSA-9013149)
  RHOF GTPase cycle (R-HSA-9035034)
  FCGR3A-mediated phagocytosis (R-HSA-9664422)
  Regulation of actin dynamics for phagocytic cup formation (R-HSA-2029482)

Molecular Interaction Atlas (MIA) of This DOT

27 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Dermatitis herpetiformis	DIS0TC0G	Definitive	Biomarker	[1]
Abdominal aortic aneurysm	DISD06OF	Strong	Biomarker	[2]
Bacillary dysentery	DISFZHKN	Strong	Altered Expression	[3]
Barrett esophagus	DIS416Y7	Strong	Genetic Variation	[4]
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[5]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[6]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[7]
Crohn disease	DIS2C5Q8	Strong	Genetic Variation	[8]
Esophageal adenocarcinoma	DISODWFP	Strong	Biomarker	[4]
Familial multiple trichoepithelioma	DISKZAUY	Strong	Genetic Variation	[4]
Familial prostate carcinoma	DISL9KNO	Strong	Biomarker	[9]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[10]
Peptic esophagitis	DISJSGBZ	Strong	Altered Expression	[4]
Prostate cancer, hereditary, 1	DISE2P4L	Strong	Biomarker	[9]
Prostate carcinoma	DISMJPLE	Strong	Genetic Variation	[9]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[1]
Skin and skin-structure infection	DIS3F9EY	Strong	Biomarker	[11]
Systemic lupus erythematosus	DISI1SZ7	Strong	Genetic Variation	[12]
Turner syndrome	DIS2035C	Strong	Genetic Variation	[13]
Ulcerative colitis	DIS8K27O	Strong	Genetic Variation	[8]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[14]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[15]
Lung cancer	DISCM4YA	moderate	Biomarker	[14]
Lung carcinoma	DISTR26C	moderate	Biomarker	[14]
Lung neoplasm	DISVARNB	moderate	Biomarker	[14]
Autoimmune disease	DISORMTM	Limited	Genetic Variation	[13]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[16]

5 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 Unconventional myosin-IXb (MYO9B).	[17]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Unconventional myosin-IXb (MYO9B).	[21]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Unconventional myosin-IXb (MYO9B).	[24]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Unconventional myosin-IXb (MYO9B).	[25]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Unconventional myosin-IXb (MYO9B).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Unconventional myosin-IXb (MYO9B).	[18]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of Unconventional myosin-IXb (MYO9B).	[19]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Unconventional myosin-IXb (MYO9B).	[20]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide decreases the expression of Unconventional myosin-IXb (MYO9B).	[22]
Exemestane	DM9HPW3	Approved	Exemestane increases the expression of Unconventional myosin-IXb (MYO9B).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Unconventional myosin-IXb (MYO9B).	[26]

References

• [1] Myosin IXB gene region and gluten intolerance: linkage to coeliac disease and a putative dermatitis herpetiformis association.J Med Genet. 2008 Apr;45(4):222-7. doi: 10.1136/jmg.2007.053991. Epub 2007 Dec 12.
• [2] Inhibition of KLF5-Myo9b-RhoA Pathway-Mediated Podosome Formation in Macrophages Ameliorates Abdominal Aortic Aneurysm.Circ Res. 2017 Mar 3;120(5):799-815. doi: 10.1161/CIRCRESAHA.116.310367. Epub 2017 Jan 23.
• [3] Functional role for the class IX myosin myr5 in epithelial cell infection by Shigella flexneri.Cell Microbiol. 2000 Dec;2(6):601-16. doi: 10.1046/j.1462-5822.2000.00084.x.
• [4] Myo9B is associated with an increased risk of Barrett's esophagus and esophageal adenocarcinoma.Scand J Gastroenterol. 2012 Dec;47(12):1422-8. doi: 10.3109/00365521.2012.722673. Epub 2012 Sep 7.
• [5] A locus on 19p13 modifies risk of breast cancer in BRCA1 mutation carriers and is associated with hormone receptor-negative breast cancer in the general population.Nat Genet. 2010 Oct;42(10):885-92. doi: 10.1038/ng.669. Epub 2010 Sep 19.
• [6] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [7] Leveraging Polygenic Functional Enrichment to Improve GWAS Power.Am J Hum Genet. 2019 Jan 3;104(1):65-75. doi: 10.1016/j.ajhg.2018.11.008. Epub 2018 Dec 27.
• [8] A meta-analysis of the relationship between MYO9B gene polymorphisms and susceptibility to Crohn's disease and ulcerative colitis.Hum Immunol. 2016 Oct;77(10):990-996. doi: 10.1016/j.humimm.2016.07.008. Epub 2016 Jul 18.
• [9] Association analyses of more than 140,000 men identify 63 new prostate cancer susceptibility loci.Nat Genet. 2018 Jul;50(7):928-936. doi: 10.1038/s41588-018-0142-8. Epub 2018 Jun 11.
• [10] Interethnic analyses of blood pressure loci in populations of East Asian and European descent.Nat Commun. 2018 Nov 28;9(1):5052. doi: 10.1038/s41467-018-07345-0.
• [11] The Rho regulator Myosin IXb enables nonlymphoid tissue seeding of protective CD8(+) T cells.J Exp Med. 2018 Jul 2;215(7):1869-1890. doi: 10.1084/jem.20170896. Epub 2018 Jun 6.
• [12] MYO9B gene polymorphisms are associated with autoimmune diseases in Spanish population.Hum Immunol. 2007 Jul;68(7):610-5. doi: 10.1016/j.humimm.2007.03.006. Epub 2007 Apr 10.
• [13] Analysis of PTPN22, ZFAT and MYO9B polymorphisms in Turner Syndrome and risk of autoimmune disease.Int J Immunogenet. 2017 Aug;44(4):153-157. doi: 10.1111/iji.12323. Epub 2017 Jun 18.
• [14] Myo9b is a key player in SLIT/ROBO-mediated lung tumor suppression.J Clin Invest. 2015 Nov 3;125(12):4407-20. doi: 10.1172/JCI81673.
• [15] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [16] Association analysis of myosin IXB and type 1 diabetes.Hum Immunol. 2010 Jun;71(6):598-601. doi: 10.1016/j.humimm.2010.03.002. Epub 2010 Apr 1.
• [17] 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.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [20] 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.
• [21] 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.
• [22] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [23] Effects of aromatase inhibitors on human osteoblast and osteoblast-like cells: a possible androgenic bone protective effects induced by exemestane. Bone. 2007 Apr;40(4):876-87. doi: 10.1016/j.bone.2006.11.029. Epub 2006 Dec 28.
• [24] 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.
• [25] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [26] Characterization of the Molecular Alterations Induced by the Prolonged Exposure of Normal Colon Mucosa and Colon Cancer Cells to Low-Dose Bisphenol A. Int J Mol Sci. 2022 Oct 1;23(19):11620. doi: 10.3390/ijms231911620.