Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT2YPT7O)

• DOT Name: Unconventional myosin-XVIIIa (MYO18A)
• Synonyms: Molecule associated with JAK3 N-terminus; MAJN; Myosin containing a PDZ domain; Surfactant protein receptor SP-R210; SP-R210
• Gene Name: MYO18A
• Related Disease:
  Acute myelogenous leukaemia
  Advanced cancer
  Hepatitis C virus infection
  Pneumonia
• UniProt ID: MY18A_HUMAN
• Pfam ID: PF00063 ; PF01576 ; PF00595
• Sequence:
  MFNLMKKDKDKDGGRKEKKEKKEKKERMSAAELRSLEEMSLRRGFFNLNRSSKRESKTRL
  EISNPIPIKVASGSDLHLTDIDSDSNRGSVILDSGHLSTASSSDDLKGEEGSFRGSVLQR
  AAKFGSLAKQNSQMIVKRFSFSQRSRDESASETSTPSEHSAAPSPQVEVRTLEGQLVQHP
  GPGIPRPGHRSRAPELVTKKFPVDLRLPPVVPLPPPTLRELELQRRPTGDFGFSLRRTTM
  LDRGPEGQACRRVVHFAEPGAGTKDLALGLVPGDRLVEINGHNVESKSRDEIVEMIRQSG
  DSVRLKVQPIPELSELSRSWLRSGEGPRREPSDAKTEEQIAAEEAWNETEKVWLVHRDGF
  SLASQLKSEELNLPEGKVRVKLDHDGAILDVDEDDVEKANAPSCDRLEDLASLVYLNESS
  VLHTLRQRYGASLLHTYAGPSLLVLGPRGAPAVYSEKVMHMFKGCRREDMAPHIYAVAQT
  AYRAMLMSRQDQSIILLGSSGSGKTTSCQHLVQYLATIAGISGNKVFSVEKWQALYTLLE
  AFGNSPTIINGNATRFSQILSLDFDQAGQVASASIQTMLLEKLRVARRPASEATFNVFYY
  LLACGDGTLRTELHLNHLAENNVFGIVPLAKPEEKQKAAQQFSKLQAAMKVLGISPDEQK
  ACWFILAAIYHLGAAGATKEAAEAGRKQFARHEWAQKAAYLLGCSLEELSSAIFKHQHKG
  GTLQRSTSFRQGPEESGLGDGTGPKLSALECLEGMAAGLYSELFTLLVSLVNRALKSSQH
  SLCSMMIVDTPGFQNPEQGGSARGASFEELCHNYTQDRLQRLFHERTFVQELERYKEENI
  ELAFDDLEPPTDDSVAAVDQASHQSLVRSLARTDEARGLLWLLEEEALVPGASEDTLLER
  LFSYYGPQEGDKKGQSPLLHSSKPHHFLLGHSHGTNWVEYNVTGWLNYTKQNPATQNAPR
  LLQDSQKKIISNLFLGRAGSATVLSGSIAGLEGGSQLALRRATSMRKTFTTGMAAVKKKS
  LCIQMKLQVDALIDTIKKSKLHFVHCFLPVAEGWAGEPRSASSRRVSSSSELDLPSGDHC
  EAGLLQLDVPLLRTQLRGSRLLDAMRMYRQGYPDHMVFSEFRRRFDVLAPHLTKKHGRNY
  IVVDERRAVEELLECLDLEKSSCCMGLSRVFFRAGTLARLEEQRDEQTSRNLTLFQAACR
  GYLARQHFKKRKIQDLAIRCVQKNIKKNKGVKDWPWWKLFTTVRPLIEVQLSEEQIRNKD
  EEIQQLRSKLEKAEKERNELRLNSDRLESRISELTSELTDERNTGESASQLLDAETAERL
  RAEKEMKELQTQYDALKKQMEVMEMEVMEARLIRAAEINGEVDDDDAGGEWRLKYERAVR
  EVDFTKKRLQQEFEDKLEVEQQNKRQLERRLGDLQADSEESQRALQQLKKKCQRLTAELQ
  DTKLHLEGQQVRNHELEKKQRRFDSELSQAHEEAQREKLQREKLQREKDMLLAEAFSLKQ
  QLEEKDMDIAGFTQKVVSLEAELQDISSQESKDEASLAKVKKQLRDLEAKVKDQEEELDE
  QAGTIQMLEQAKLRLEMEMERMRQTHSKEMESRDEEVEEARQSCQKKLKQMEVQLEEEYE
  DKQKVLREKRELEGKLATLSDQVNRRDFESEKRLRKDLKRTKALLADAQLMLDHLKNSAP
  SKREIAQLKNQLEESEFTCAAAVKARKAMEVEIEDLHLQIDDIAKAKTALEEQLSRLQRE
  KNEIQNRLEEDQEDMNELMKKHKAAVAQASRDLAQINDLQAQLEEANKEKQELQEKLQAL
  QSQVEFLEQSMVDKSLVSRQEAKIRELETRLEFERTQVKRLESLASRLKENMEKLTEERD
  QRIAAENREKEQNKRLQRQLRDTKEEMGELARKEAEASRKKHELEMDLESLEAANQSLQA
  DLKLAFKRIGDLQAAIEDEMESDENEDLINSLQDMVTKYQKRKNKLEGDSDVDSELEDRV
  DGVKSWLSKNKGPSKAASDDGSLKSSSPTSYWKSLAPDRSDDEHDPLDNTSRPRYSHSYL
  SDSDTEAKLTETNA
• Function: May link Golgi membranes to the cytoskeleton and participate in the tensile force required for vesicle budding from the Golgi. Thereby, may play a role in Golgi membrane trafficking and could indirectly give its flattened shape to the Golgi apparatus. Alternatively, in concert with LURAP1 and CDC42BPA/CDC42BPB, has been involved in modulating lamellar actomyosin retrograde flow that is crucial to cell protrusion and migration. May be involved in the maintenance of the stromal cell architectures required for cell to cell contact. Regulates trafficking, expression, and activation of innate immune receptors on macrophages. Plays a role to suppress inflammatory responsiveness of macrophages via a mechanism that modulates CD14 trafficking. Acts as a receptor of surfactant-associated protein A (SFTPA1/SP-A) and plays an important role in internalization and clearance of SFTPA1-opsonized S.aureus by alveolar macrophages. Strongly enhances natural killer cell cytotoxicity.
• KEGG Pathway: Motor proteins (hsa04814)
• Reactome Pathway:
  Signaling by FGFR1 in disease (R-HSA-5655302)
  Signaling by FLT3 fusion proteins (R-HSA-9703465)
  Signaling by cytosolic FGFR1 fusion mutants (R-HSA-1839117)

Molecular Interaction Atlas (MIA) of This DOT

4 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute myelogenous leukaemia	DISCSPTN	Definitive	Genetic Variation	[1]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Posttranslational Modification	[3]
Pneumonia	DIS8EF3M	Limited	Biomarker	[4]

6 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-XVIIIa (MYO18A).	[5]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Unconventional myosin-XVIIIa (MYO18A).	[9]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Unconventional myosin-XVIIIa (MYO18A).	[18]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Unconventional myosin-XVIIIa (MYO18A).	[20]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Unconventional myosin-XVIIIa (MYO18A).	[21]
Coumarin	DM0N8ZM	Investigative	Coumarin affects the phosphorylation of Unconventional myosin-XVIIIa (MYO18A).	[20]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Unconventional myosin-XVIIIa (MYO18A).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Unconventional myosin-XVIIIa (MYO18A).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Unconventional myosin-XVIIIa (MYO18A).	[8]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of Unconventional myosin-XVIIIa (MYO18A).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Unconventional myosin-XVIIIa (MYO18A).	[11]
Decitabine	DMQL8XJ	Approved	Decitabine decreases the expression of Unconventional myosin-XVIIIa (MYO18A).	[12]
Selenium	DM25CGV	Approved	Selenium increases the expression of Unconventional myosin-XVIIIa (MYO18A).	[13]
Menthol	DMG2KW7	Approved	Menthol increases the expression of Unconventional myosin-XVIIIa (MYO18A).	[14]
Aminoglutethimide	DMWFHMZ	Approved	Aminoglutethimide decreases the expression of Unconventional myosin-XVIIIa (MYO18A).	[15]
Resveratrol	DM3RWXL	Phase 3	Resveratrol decreases the expression of Unconventional myosin-XVIIIa (MYO18A).	[16]
Curcumin	DMQPH29	Phase 3	Curcumin increases the expression of Unconventional myosin-XVIIIa (MYO18A).	[17]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Unconventional myosin-XVIIIa (MYO18A).	[8]
Tocopherol	DMBIJZ6	Phase 2	Tocopherol increases the expression of Unconventional myosin-XVIIIa (MYO18A).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Unconventional myosin-XVIIIa (MYO18A).	[19]

References

• [1] A three-way translocation of MLL, MLLT11, and the novel reciprocal partner gene MYO18A in a child with acute myeloid leukemia.Cancer Genet. 2012 May;205(5):261-5. doi: 10.1016/j.cancergen.2012.02.006.
• [2] Emerging themes of regulation at the Golgi.Curr Opin Cell Biol. 2017 Apr;45:17-23. doi: 10.1016/j.ceb.2017.01.004. Epub 2017 Feb 16.
• [3] Role of phosphatidylinositol 4-phosphate (PI4P) and its binding protein GOLPH3 in hepatitis C virus secretion.J Biol Chem. 2012 Aug 10;287(33):27637-47. doi: 10.1074/jbc.M112.346569. Epub 2012 Jun 28.
• [4] Surfactant protein A (SP-A)-mediated clearance of Staphylococcus aureus involves binding of SP-A to the staphylococcal adhesin eap and the macrophage receptors SP-A receptor 210 and scavenger receptor class A.J Biol Chem. 2011 Feb 11;286(6):4854-70. doi: 10.1074/jbc.M110.125567. Epub 2010 Dec 1.
• [5] 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.
• [6] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] 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.
• [9] 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.
• [10] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [11] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [12] DNA methylation inhibits p53-mediated survivin repression. Oncogene. 2009 May 14;28(19):2046-50. doi: 10.1038/onc.2009.62. Epub 2009 Apr 13.
• [13] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [14] Repurposing L-menthol for systems medicine and cancer therapeutics? L-menthol induces apoptosis through caspase 10 and by suppressing HSP90. OMICS. 2016 Jan;20(1):53-64.
• [15] Proteomic profile of aminoglutethimide-induced apoptosis in HL-60 cells: role of myeloperoxidase and arylamine free radicals. Chem Biol Interact. 2015 Sep 5;239:129-38.
• [16] Differential expression of genes induced by resveratrol in LNCaP cells: P53-mediated molecular targets. Int J Cancer. 2003 Mar 20;104(2):204-12.
• [17] Curcumin restores corticosteroid function in monocytes exposed to oxidants by maintaining HDAC2. Am J Respir Cell Mol Biol. 2008 Sep;39(3):312-23. doi: 10.1165/rcmb.2008-0012OC. Epub 2008 Apr 17.
• [18] 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.
• [19] 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.
• [20] 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.
• [21] 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.