Details of Drug Off-Target (DOT)

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

• DOT Name: Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1)
• Synonyms: CCP module-containing protein 22; Polydom; Selectin-like osteoblast-derived protein; SEL-OB; Serologically defined breast cancer antigen NY-BR-38
• Gene Name: SVEP1
• Related Disease:
  Carcinoma of liver and intrahepatic biliary tract
  Bipolar disorder
  Breast carcinoma
  Cardiovascular disease
  Coronary heart disease
  High blood pressure
  Neoplasm
  Hirschsprung disease
  Liver cancer
  Polycystic ovarian syndrome
• UniProt ID: SVEP1_HUMAN
• Pfam ID: PF00008 ; PF07645 ; PF07699 ; PF12661 ; PF02494 ; PF00354 ; PF00084 ; PF00092
• Sequence:
  MWPRLAFCCWGLALVSGWATFQQMSPSRNFSFRLFPETAPGAPGSIPAPPAPGDEAAGSR
  VERLGQAFRRRVRLLRELSERLELVFLVDDSSSVGEVNFRSELMFVRKLLSDFPVVPTAT
  RVAIVTFSSKNYVVPRVDYISTRRARQHKCALLLQEIPAISYRGGGTYTKGAFQQAAQIL
  LHARENSTKVVFLITDGYSNGGDPRPIAASLRDSGVEIFTFGIWQGNIRELNDMASTPKE
  EHCYLLHSFEEFEALARRALHEDLPSGSFIQDDMVHCSYLCDEGKDCCDRMGSCKCGTHT
  GHFECICEKGYYGKGLQYECTACPSGTYKPEGSPGGISSCIPCPDENHTSPPGSTSPEDC
  VCREGYRASGQTCELVHCPALKPPENGYFIQNTCNNHFNAACGVRCHPGFDLVGSSIILC
  LPNGLWSGSESYCRVRTCPHLRQPKHGHISCSTREMLYKTTCLVACDEGYRLEGSDKLTC
  QGNSQWDGPEPRCVERHCSTFQMPKDVIISPHNCGKQPAKFGTICYVSCRQGFILSGVKE
  MLRCTTSGKWNVGVQAAVCKDVEAPQINCPKDIEAKTLEQQDSANVTWQIPTAKDNSGEK
  VSVHVHPAFTPPYLFPIGDVAIVYTATDLSGNQASCIFHIKVIDAEPPVIDWCRSPPPVQ
  VSEKVHAASWDEPQFSDNSGAELVITRSHTQGDLFPQGETIVQYTATDPSGNNRTCDIHI
  VIKGSPCEIPFTPVNGDFICTPDNTGVNCTLTCLEGYDFTEGSTDKYYCAYEDGVWKPTY
  TTEWPDCAKKRFANHGFKSFEMFYKAARCDDTDLMKKFSEAFETTLGKMVPSFCSDAEDI
  DCRLEENLTKKYCLEYNYDYENGFAIGPGGWGAANRLDYSYDDFLDTVQETATSIGNAKS
  SRIKRSAPLSDYKIKLIFNITASVPLPDERNDTLEWENQQRLLQTLETITNKLKRTLNKD
  PMYSFQLASEILIADSNSLETKKASPFCRPGSVLRGRMCVNCPLGTYYNLEHFTCESCRI
  GSYQDEEGQLECKLCPSGMYTEYIHSRNISDCKAQCKQGTYSYSGLETCESCPLGTYQPK
  FGSRSCLSCPENTSTVKRGAVNISACGVPCPEGKFSRSGLMPCHPCPRDYYQPNAGKAFC
  LACPFYGTTPFAGSRSITECSSFSSTFSAAEESVVPPASLGHIKKRHEISSQVFHECFFN
  PCHNSGTCQQLGRGYVCLCPLGYTGLKCETDIDECSPLPCLNNGVCKDLVGEFICECPSG
  YTGQRCEENINECSSSPCLNKGICVDGVAGYRCTCVKGFVGLHCETEVNECQSNPCLNNA
  VCEDQVGGFLCKCPPGFLGTRCGKNVDECLSQPCKNGATCKDGANSFRCLCAAGFTGSHC
  ELNINECQSNPCRNQATCVDELNSYSCKCQPGFSGKRCETEQSTGFNLDFEVSGIYGYVM
  LDGMLPSLHALTCTFWMKSSDDMNYGTPISYAVDNGSDNTLLLTDYNGWVLYVNGREKIT
  NCPSVNDGRWHHIAITWTSANGIWKVYIDGKLSDGGAGLSVGLPIPGGGALVLGQEQDKK
  GEGFSPAESFVGSISQLNLWDYVLSPQQVKSLATSCPEELSKGNVLAWPDFLSGIVGKVK
  IDSKSIFCSDCPRLGGSVPHLRTASEDLKPGSKVNLFCDPGFQLVGNPVQYCLNQGQWTQ
  PLPHCERISCGVPPPLENGFHSADDFYAGSTVTYQCNNGYYLLGDSRMFCTDNGSWNGVS
  PSCLDVDECAVGSDCSEHASCLNVDGSYICSCVPPYTGDGKNCAEPIKCKAPGNPENGHS
  SGEIYTVGAEVTFSCQEGYQLMGVTKITCLESGEWNHLIPYCKAVSCGKPAIPENGCIEE
  LAFTFGSKVTYRCNKGYTLAGDKESSCLANSSWSHSPPVCEPVKCSSPENINNGKYILSG
  LTYLSTASYSCDTGYSLQGPSIIECTASGIWDRAPPACHLVFCGEPPAIKDAVITGNNFT
  FRNTVTYTCKEGYTLAGLDTIECLADGKWSRSDQQCLAVSCDEPPIVDHASPETAHRLFG
  DIAFYYCSDGYSLADNSQLLCNAQGKWVPPEGQDMPRCIAHFCEKPPSVSYSILESVSKA
  KFAAGSVVSFKCMEGFVLNTSAKIECMRGGQWNPSPMSIQCIPVRCGEPPSIMNGYASGS
  NYSFGAMVAYSCNKGFYIKGEKKSTCEATGQWSSPIPTCHPVSCGEPPKVENGFLEHTTG
  RIFESEVRYQCNPGYKSVGSPVFVCQANRHWHSESPLMCVPLDCGKPPPIQNGFMKGENF
  EVGSKVQFFCNEGYELVGDSSWTCQKSGKWNKKSNPKCMPAKCPEPPLLENQLVLKELTT
  EVGVVTFSCKEGHVLQGPSVLKCLPSQQWNDSFPVCKIVLCTPPPLISFGVPIPSSALHF
  GSTVKYSCVGGFFLRGNSTTLCQPDGTWSSPLPECVPVECPQPEEIPNGIIDVQGLAYLS
  TALYTCKPGFELVGNTTTLCGENGHWLGGKPTCKAIECLKPKEILNGKFSYTDLHYGQTV
  TYSCNRGFRLEGPSALTCLETGDWDVDAPSCNAIHCDSPQPIENGFVEGADYSYGAIIIY
  SCFPGFQVAGHAMQTCEESGWSSSIPTCMPIDCGLPPHIDFGDCTKLKDDQGYFEQEDDM
  MEVPYVTPHPPYHLGAVAKTWENTKESPATHSSNFLYGTMVSYTCNPGYELLGNPVLICQ
  EDGTWNGSAPSCISIECDLPTAPENGFLRFTETSMGSAVQYSCKPGHILAGSDLRLCLEN
  RKWSGASPRCEAISCKKPNPVMNGSIKGSNYTYLSTLYYECDPGYVLNGTERRTCQDDKN
  WDEDEPICIPVDCSSPPVSANGQVRGDEYTFQKEIEYTCNEGFLLEGARSRVCLANGSWS
  GATPDCVPVRCATPPQLANGVTEGLDYGFMKEVTFHCHEGYILHGAPKLTCQSDGNWDAE
  IPLCKPVNCGPPEDLAHGFPNGFSFIHGGHIQYQCFPGYKLHGNSSRRCLSNGSWSGSSP
  SCLPCRCSTPVIEYGTVNGTDFDCGKAARIQCFKGFKLLGLSEITCEADGQWSSGFPHCE
  HTSCGSLPMIPNAFISETSSWKENVITYSCRSGYVIQGSSDLICTEKGVWSQPYPVCEPL
  SCGSPPSVANAVATGEAHTYESEVKLRCLEGYTMDTDTDTFTCQKDGRWFPERISCSPKK
  CPLPENITHILVHGDDFSVNRQVSVSCAEGYTFEGVNISVCQLDGTWEPPFSDESCSPVS
  CGKPESPEHGFVVGSKYTFESTIIYQCEPGYELEGNRERVCQENRQWSGGVAICKETRCE
  TPLEFLNGKADIENRTTGPNVVYSCNRGYSLEGPSEAHCTENGTWSHPVPLCKPNPCPVP
  FVIPENALLSEKEFYVDQNVSIKCREGFLLQGHGIITCNPDETWTQTSAKCEKISCGPPA
  HVENAIARGVHYQYGDMITYSCYSGYMLEGFLRSVCLENGTWTSPPICRAVCRFPCQNGG
  ICQRPNACSCPEGWMGRLCEEPICILPCLNGGRCVAPYQCDCPPGWTGSRCHTAVCQSPC
  LNGGKCVRPNRCHCLSSWTGHNCSRKRRTGF
• Function: Required for morphological development, cell alignment and migration of lymphatic endothelial cells during embryonic development, potentially via modulation of ANGPT2-TIE1 signaling and subsequent activation of FOXC2 transcription. Required for embryonic lymphatic vascular development, via mediating the correct formation of the first lymphovenous contact site and tight association of the lymphatic endothelium with the venous endothelium. Represses PRKCA-mediated L-type voltage-gated channel Ca(2+) influx and ROCK-mediated calcium sensitivity in vascular smooth muscle cells, via its interaction with integrins, thereby inhibiting vasocontraction. Promotes platelet activation, via its interaction with PEAR1 and subsequent activation of AKT/mTOR signaling. Plays a role in epidermal development and keratinocyte differentiation, independent of cell-cell adhesion. May play a role in initial cell attachment of stromal osteogenic cells. May promote myoblast cell adhesion when in the presence of integrin ITGA9:ITGB1.
• Tissue Specificity: Expressed in mesenchymal cells (at protein level) . Expressed in vascular smooth muscle cells (at protein level) . Expressed throughout the epidermis, expression is most prominent in the basal and lower suprabasal layers of the epidermis and in dermal fibroblasts in the upper dermis (at protein level) . Abundantly expressed in the placenta, weakly expressed in heart and skeletal muscle . Also expressed in the lung, adrenal gland and cerebellum .

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Carcinoma of liver and intrahepatic biliary tract	DIS8WA0W	Definitive	Genetic Variation	[1]
Bipolar disorder	DISAM7J2	Strong	Genetic Variation	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[3]
Cardiovascular disease	DIS2IQDX	Strong	Genetic Variation	[4]
Coronary heart disease	DIS5OIP1	Strong	Genetic Variation	[5]
High blood pressure	DISY2OHH	Strong	Genetic Variation	[2]
Neoplasm	DISZKGEW	Strong	Biomarker	[3]
Hirschsprung disease	DISUUSM1	moderate	Biomarker	[6]
Liver cancer	DISDE4BI	Disputed	Genetic Variation	[1]
Polycystic ovarian syndrome	DISZ2BNG	Limited	Genetic Variation	[7]

1 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 Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[8]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[9]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[10]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[11]
Estradiol	DMUNTE3	Approved	Estradiol affects the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[12]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[13]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[14]
Dexamethasone	DMMWZET	Approved	Dexamethasone increases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[15]
Cytarabine	DMZD5QR	Approved	Cytarabine decreases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[16]
Dasatinib	DMJV2EK	Approved	Dasatinib increases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[18]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide decreases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[19]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde decreases the expression of Sushi, von Willebrand factor type A, EGF and pentraxin domain-containing protein 1 (SVEP1).	[21]

References

• [1] A novel knowledge-derived data potentizing method revealed unique liver cancer-associated genetic variants.Hum Genomics. 2019 Jul 4;13(1):30. doi: 10.1186/s40246-019-0213-7.
• [2] Leveraging electronic health records to study pleiotropic effects on bipolar disorder and medical comorbidities.Transl Psychiatry. 2016 Aug 16;6(8):e870. doi: 10.1038/tp.2016.138.
• [3] SVEP1 expression is regulated in estrogen-dependent manner.J Cell Physiol. 2007 Mar;210(3):732-9. doi: 10.1002/jcp.20895.
• [4] 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.
• [5] 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.
• [6] Fine mapping of the 9q31 Hirschsprung's disease locus.Hum Genet. 2010 Jun;127(6):675-83. doi: 10.1007/s00439-010-0813-8. Epub 2010 Apr 2.
• [7] Epigenetic and Transcriptional Alterations in Human Adipose Tissue of Polycystic Ovary Syndrome.Sci Rep. 2016 Mar 15;6:22883. doi: 10.1038/srep22883.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [12] Identification of novel low-dose bisphenol a targets in human foreskin fibroblast cells derived from hypospadias patients. PLoS One. 2012;7(5):e36711. doi: 10.1371/journal.pone.0036711. Epub 2012 May 4.
• [13] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [14] The exosome-like vesicles derived from androgen exposed-prostate stromal cells promote epithelial cells proliferation and epithelial-mesenchymal transition. Toxicol Appl Pharmacol. 2021 Jan 15;411:115384. doi: 10.1016/j.taap.2020.115384. Epub 2020 Dec 25.
• [15] Identification of mechanisms of action of bisphenol a-induced human preadipocyte differentiation by transcriptional profiling. Obesity (Silver Spring). 2014 Nov;22(11):2333-43.
• [16] Cytosine arabinoside induces ectoderm and inhibits mesoderm expression in human embryonic stem cells during multilineage differentiation. Br J Pharmacol. 2011 Apr;162(8):1743-56.
• [17] Dasatinib reverses cancer-associated fibroblasts (CAFs) from primary lung carcinomas to a phenotype comparable to that of normal fibroblasts. Mol Cancer. 2010 Jun 27;9:168.
• [18] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] 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.
• [21] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.