Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5G38CH)

• DOT Name: Multiple epidermal growth factor-like domains protein 8 (MEGF8)
• Synonyms: Multiple EGF-like domains protein 8; Epidermal growth factor-like protein 4; EGF-like protein 4
• Gene Name: MEGF8
• Related Disease:
  Lung adenocarcinoma
  RAB23-related Carpenter syndrome
  Advanced cancer
  Chronic kidney disease
  Colitis
  Colorectal carcinoma
  Colorectal neoplasm
  Coronary heart disease
  Crohn disease
  Endometriosis
  Epithelial ovarian cancer
  Female hypogonadism
  Gastric cancer
  Hepatocellular carcinoma
  Intrahepatic cholangiocarcinoma
  MEGF8-related Carpenter syndrome
  Neoplasm
  Ovarian cancer
  Ovarian neoplasm
  Polydactyly
  Stomach cancer
  Carpenter syndrome
  Esophageal adenocarcinoma
  Familial multiple trichoepithelioma
  Parkinson disease
• UniProt ID: MEGF8_HUMAN
• Pfam ID: PF00431 ; PF12947 ; PF07645 ; PF13415 ; PF13418 ; PF13854 ; PF00053 ; PF01437
• Sequence:
  MALGKVLAMALVLALAVLGSLSPGARAGDCKGQRQVLREAPGFVTDGAGNYSVNGNCEWL
  IEAPSPQHRILLDFLFLDTECTYDYLFVYDGDSPRGPLLASLSGSTRPPPIEASSGKMLL
  HLFSDANYNLLGFNASFRFSLCPGGCQSHGQCQPPGVCACEPGWGGPDCGLQECSAYCGS
  HGTCASPLGPCRCEPGFLGRACDLHLWENQGAGWWHNVSARDPAFSARIGAAGAFLSPPG
  LLAVFGGQDLNNALGDLVLYNFSANTWESWDLSPAPAARHSHVAVAWAGSLVLMGGELAD
  GSLTNDVWAFSPLGRGHWELLAPPASSSSGPPGLAGHAAALVDDVWLYVSGGRTPHDLFS
  SGLFRFRLDSTSGGYWEQVIPAGGRPPAATGHSMVFHAPSRALLVHGGHRPSTARFSVRV
  NSTELFHVDRHVWTTLKGRDGLQGPRERAFHTASVLGNYMVVYGGNVHTHYQEEKCYEDG
  IFFYHLGCHQWVSGAELAPPGTPEGRAAPPSGRYSHVAAVLGGSVLLVAGGYSGRPRGDL
  MAYKVPPFVFQAPAPDYHLDYCSMYTDHSVCSRDPECSWCQGACQAAPPPGTPLGACPAA
  SCLGLGRLLGDCQACLAFSSPTAPPRGPGTLGWCVHNESCLPRPEQARCRGEQISGTVGW
  WGPAPVFVTSLEACVTQSFLPGLHLLTFQQPPNTSQPDKVSIVRSTTITLTPSAETDVSL
  VYRGFIYPMLPGGPGGPGAEDVAVWTRAQRLHVLARMARGPDTENMEEVGRWVAHQEKET
  RRLQRPGSARLFPLPGRDHKYAVEIQGQLNGSAGPGHSELTLLWDRTGVPGGSEISFFFL
  EPYRSSSCTSYSSCLGCLADQGCGWCLTSATCHLRQGGAHCGDDGAGGSLLVLVPTLCPL
  CEEHRDCHACTQDPFCEWHQSTSRKGDAACSRRGRGRGALKSPEECPPLCSQRLTCEDCL
  ANSSQCAWCQSTHTCFLFAAYLARYPHGGCRGWDDSVHSEPRCRSCDGFLTCHECLQSHE
  CGWCGNEDNPTLGRCLQGDFSGPLGGGNCSLWVGEGLGLPVALPARWAYARCPDVDECRL
  GLARCHPRATCLNTPLSYECHCQRGYQGDGISHCNRTCLEDCGHGVCSGPPDFTCVCDLG
  WTSDLPPPTPAPGPPAPRCSRDCGCSFHSHCRKRGPGFCDECQDWTWGEHCERCRPGSFG
  NATGSRGCRPCQCNGHGDPRRGHCDNLSGLCFCQDHTEGAHCQLCSPGYYGDPRAGGSCF
  RECGGRALLTNVSSVALGSRRVGGLLPPGGGAARAGPGLSYCVWVVSATEELQPCAPGTL
  CPPLTLTFSPDSSTPCTLSYVLAFDGFPRFLDTGVVQSDRSLIAAFCGQRRDRPLTVQAL
  SGLLVLHWEANGSSSWGFNASVGSARCGSGGPGSCPVPQECVPQDGAAGAGLCRCPQGWA
  GPHCRMALCPENCNAHTGAGTCNQSLGVCICAEGFGGPDCATKLDGGQLVWETLMDSRLS
  ADTASRFLHRLGHTMVDGPDATLWMFGGLGLPQGLLGNLYRYSVSERRWTQMLAGAEDGG
  PGPSPRSFHAAAYVPAGRGAMYLLGGLTAGGVTRDFWVLNLTTLQWRQEKAPQTVELPAV
  AGHTLTARRGLSLLLVGGYSPENGFNQQLLEYQLATGTWVSGAQSGTPPTGLYGHSAVYH
  EATDSLYVFGGFRFHVELAAPSPELYSLHCPDRTWSLLAPSQGAKRDRMRNVRGSSRGLG
  QVPGEQPGSWGFREVRKKMALWAALAGTGGFLEEISPHLKEPRPRLFHASALLGDTMVVL
  GGRSDPDEFSSDVLLYQVNCNAWLLPDLTRSASVGPPMEESVAHAVAAVGSRLYISGGFG
  GVALGRLLALTLPPDPCRLLSSPEACNQSGACTWCHGACLSGDQAHRLGCGGSPCSPMPR
  SPEECRRLRTCSECLARHPRTLQPGDGEASTPRCKWCTNCPEGACIGRNGSCTSENDCRI
  NQREVFWAGNCSEAACGAADCEQCTREGKCMWTRQFKRTGETRRILSVQPTYDWTCFSHS
  LLNVSPMPVESSPPLPCPTPCHLLPNCTSCLDSKGADGGWQHCVWSSSLQQCLSPSYLPL
  RCMAGGCGRLLRGPESCSLGCAQATQCALCLRRPHCGWCAWGGQDGGGRCMEGGLSGPRD
  GLTCGRPGASWAFLSCPPEDECANGHHDCNETQNCHDQPHGYECSCKTGYTMDNMTGLCR
  PVCAQGCVNGSCVEPDHCRCHFGFVGRNCSTECRCNRHSECAGVGARDHCLLCRNHTKGS
  HCEQCLPLFVGSAVGGGTCRPCHAFCRGNSHICISRKELQMSKGEPKKYSLDPEEIENWV
  TEGPSEDEAVCVNCQNNSYGEKCESCLQGYFLLDGKCTKCQCNGHADTCNEQDGTGCPCQ
  NNTETGTCQGSSPSDRRDCYKYQCAKCRESFHGSPLGGQQCYRLISVEQECCLDPTSQTN
  CFHEPKRRALGPGRTVLFGVQPKFTNVDIRLTLDVTFGAVDLYVSTSYDTFVVRVAPDTG
  VHTVHIQPPPAPPPPPPPADGGPRGAGDPGGAGASSGPGAPAEPRVREVWPRGLITYVTV
  TEPSAVLVVRGVRDRLVITYPHEHHALKSSRFYLLLLGVGDPSGPGANGSADSQGLLFFR
  QDQAHIDLFVFFSVFFSCFFLFLSLCVLLWKAKQALDQRQEQRRHLQEMTKMASRPFAKV
  TVCFPPDPTAPASAWKPAGLPPPAFRRSEPFLAPLLLTGAGGPWGPMGGGCCPPAIPATT
  AGLRAGPITLEPTEDGMAGVATLLLQLPGGPHAPNGACLGSALVTLRHRLHEYCGGGGGA
  GGSGHGTGAGRKGLLSQDNLTSMSL
• Function: Acts as a negative regulator of hedgehog signaling.
• KEGG Pathway: Hedgehog sig.ling pathway (hsa04340)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Lung adenocarcinoma	DISD51WR	Definitive	Altered Expression	[1]
RAB23-related Carpenter syndrome	DISR9P09	Definitive	Autosomal recessive	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Chronic kidney disease	DISW82R7	Strong	Biomarker	[4]
Colitis	DISAF7DD	Strong	Altered Expression	[5]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[6]
Colorectal neoplasm	DISR1UCN	Strong	Altered Expression	[7]
Coronary heart disease	DIS5OIP1	Strong	Biomarker	[8]
Crohn disease	DIS2C5Q8	Strong	Biomarker	[5]
Endometriosis	DISX1AG8	Strong	Biomarker	[9]
Epithelial ovarian cancer	DIS56MH2	Strong	Biomarker	[9]
Female hypogonadism	DISWASB4	Strong	Biomarker	[9]
Gastric cancer	DISXGOUK	Strong	Biomarker	[10]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Intrahepatic cholangiocarcinoma	DIS6GOC8	Strong	Altered Expression	[12]
MEGF8-related Carpenter syndrome	DIS3D9MI	Strong	Autosomal recessive	[13]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Ovarian cancer	DISZJHAP	Strong	Biomarker	[9]
Ovarian neoplasm	DISEAFTY	Strong	Biomarker	[9]
Polydactyly	DIS25BMZ	Strong	Biomarker	[14]
Stomach cancer	DISKIJSX	Strong	Biomarker	[10]
Carpenter syndrome	DISU690E	Supportive	Autosomal recessive	[14]
Esophageal adenocarcinoma	DISODWFP	Limited	Genetic Variation	[15]
Familial multiple trichoepithelioma	DISKZAUY	Limited	Biomarker	[15]
Parkinson disease	DISQVHKL	Limited	Biomarker	[16]

8 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 Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[17]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[18]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[19]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[21]
Marinol	DM70IK5	Approved	Marinol increases the expression of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[23]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[24]
GALLICACID	DM6Y3A0	Investigative	GALLICACID increases the expression of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[25]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Multiple epidermal growth factor-like domains protein 8 (MEGF8).	[20]

References

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• [2] Flexible and scalable diagnostic filtering of genomic variants using G2P with Ensembl VEP. Nat Commun. 2019 May 30;10(1):2373. doi: 10.1038/s41467-019-10016-3.
• [3] Selenium-Binding Protein 1 in Human Health and Disease.Int J Mol Sci. 2018 Nov 2;19(11):3437. doi: 10.3390/ijms19113437.
• [4] Identification of an argpyrimidine-modified protein in human red blood cells from schizophrenic patients: A possible biomarker for diseases involving carbonyl stress.Biochem Biophys Res Commun. 2017 Nov 4;493(1):573-577. doi: 10.1016/j.bbrc.2017.08.150. Epub 2017 Sep 1.
• [5] DNA Methylation of miR-122 Aggravates Oxidative Stress in Colitis Targeting SELENBP1 Partially by p65NF-B Signaling.Oxid Med Cell Longev. 2019 Mar 24;2019:5294105. doi: 10.1155/2019/5294105. eCollection 2019.
• [6] Transcriptional regulation and biological functions of selenium-binding protein 1 in colorectal cancer in vitro and in nude mouse xenografts.PLoS One. 2009 Nov 16;4(11):e7774. doi: 10.1371/journal.pone.0007774.
• [7] Expression of selenium-binding protein 1 characterizes intestinal cell maturation and predicts survival for patients with colorectal cancer.Mol Nutr Food Res. 2008 Nov;52(11):1289-99. doi: 10.1002/mnfr.200700331.
• [8] Efficacy and safety of the Shexiang Baoxin Pill for the treatment of coronary artery disease not amenable to revascularisation: study protocol for a randomised, placebo-controlled, double-blinded trial.BMJ Open. 2018 Feb 14;8(2):e018052. doi: 10.1136/bmjopen-2017-018052.
• [9] Selenium-Binding Protein 1 (SBP1) autoantibodies in ovarian disorders and ovarian cancer.Reproduction. 2017 Mar;153(3):277-284. doi: 10.1530/REP-16-0265. Epub 2016 Dec 13.
• [10] Selenium-binding protein 1 may decrease gastric cellular proliferation and migration.Int J Oncol. 2013 May;42(5):1620-9. doi: 10.3892/ijo.2013.1850. Epub 2013 Mar 7.
• [11] Invasive potential of hepatocellular carcinoma is enhanced by loss of selenium-binding protein 1 and subsequent upregulation of CXCR4.Am J Cancer Res. 2018 Jun 1;8(6):1040-1049. eCollection 2018.
• [12] Reduced selenium-binding protein 1 correlates with a poor prognosis in intrahepatic cholangiocarcinoma and promotes the cell epithelial-mesenchymal transition.Am J Transl Res. 2018 Nov 15;10(11):3567-3578. eCollection 2018.
• [13] Massively parallel sequencing identifies the gene Megf8 with ENU-induced mutation causing heterotaxy. Proc Natl Acad Sci U S A. 2009 Mar 3;106(9):3219-24. doi: 10.1073/pnas.0813400106. Epub 2009 Feb 13.
• [14] Mutations in multidomain protein MEGF8 identify a Carpenter syndrome subtype associated with defective lateralization. Am J Hum Genet. 2012 Nov 2;91(5):897-905. doi: 10.1016/j.ajhg.2012.08.027. Epub 2012 Oct 11.
• [15] Decreased selenium-binding protein 1 in esophageal adenocarcinoma results from posttranscriptional and epigenetic regulation and affects chemosensitivity.Clin Cancer Res. 2010 Apr 1;16(7):2009-21. doi: 10.1158/1078-0432.CCR-09-2801. Epub 2010 Mar 23.
• [16] Targeted discovery and validation of plasma biomarkers of Parkinson's disease.J Proteome Res. 2014 Nov 7;13(11):4535-45. doi: 10.1021/pr500421v. Epub 2014 Jun 11.
• [17] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [18] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [19] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [20] 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.
• [21] 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.
• [22] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [23] New insights into BaP-induced toxicity: role of major metabolites in transcriptomics and contribution to hepatocarcinogenesis. Arch Toxicol. 2016 Jun;90(6):1449-58.
• [24] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [25] Gene expression profile analysis of gallic acid-induced cell death process. Sci Rep. 2021 Aug 18;11(1):16743. doi: 10.1038/s41598-021-96174-1.