Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTP2IN12)

• DOT Name: E3 ubiquitin-protein ligase HECW2 (HECW2)
• Synonyms: EC 2.3.2.26; HECT, C2 and WW domain-containing protein 2; HECT-type E3 ubiquitin transferase HECW2; NEDD4-like E3 ubiquitin-protein ligase 2
• Gene Name: HECW2
• Related Disease:
  Cervical cancer
  Cervical carcinoma
  Colon cancer
  Colon carcinoma
  Complex neurodevelopmental disorder
  Neurodevelopmental disorder with hypotonia, seizures, and absent language
  Alzheimer disease
  Epilepsy
  Intellectual disability
  Neurodevelopmental disorder
  Emery-Dreifuss muscular dystrophy
  Schizophrenia
• UniProt ID: HECW2_HUMAN
• PDB ID: 2LFE
• EC Number: 2.3.2.26
• Pfam ID: PF00168 ; PF00632 ; PF18436 ; PF16562 ; PF00397
• Sequence:
  MASSAREHLLFVRRRNPQMRYTLSPENLQSLAAQSSMPENMTLQRANSDTDLVTSESRSS
  LTASMYEYTLGQAQNLIIFWDIKEEVDPSDWIGLYHIDENSPANFWDSKNRGVTGTQKGQ
  IVWRIEPGPYFMEPEIKICFKYYHGISGALRATTPCITVKNPAVMMGAEGMEGGASGNLH
  SRKLVSFTLSDLRAVGLKKGMFFNPDPYLKMSIQPGKKSSFPTCAHHGQERRSTIISNTT
  NPIWHREKYSFFALLTDVLEIEIKDKFAKSRPIIKRFLGKLTIPVQRLLERQAIGDQMLS
  YNLGRRLPADHVSGYLQFKVEVTSSVHEDASPEAVGTILGVNSVNGDLGSPSDDEDMPGS
  HHDSQVCSNGPVSEDSAADGTPKHSFRTSSTLEIDTEELTSTSSRTSPPRGRQDSLNDYL
  DAIEHNGHSRPGTATCSERSMGASPKLRSSFPTDTRLNAMLHIDSDEEDHEFQQDLGYPS
  SLEEEGGLIMFSRASRADDGSLTSQTKLEDNPVENEEASTHEAASFEDKPENLPELAESS
  LPAGPAPEEGEGGPEPQPSADQGSAELCGSQEVDQPTSGADTGTSDASGGSRRAVSETES
  LDQGSEPSQVSSETEPSDPARTESVSEASTRPEGESDLECADSSCNESVTTQLSSVDTRC
  SSLESARFPETPAFSSQEEEDGACAAEPTSSGPAEGSQESVCTAGSLPVVQVPSGEDEGP
  GAESATVPDQEELGEVWQRRGSLEGAAAAAESPPQEEGSAGEAQGTCEGATAQEEGATGG
  SQANGHQPLRSLPSVRQDVSRYQRVDEALPPNWEARIDSHGRIFYVDHVNRTTTWQRPTA
  PPAPQVLQRSNSIQQMEQLNRRYQSIRRTMTNERPEENTNAIDGAGEEADFHQASADFRR
  ENILPHSTSRSRITLLLQSPPVKFLISPEFFTVLHSNPSAYRMFTNNTCLKHMITKVRRD
  THHFERYQHNRDLVGFLNMFANKQLELPRGWEMKHDHQGKAFFVDHNSRTTTFIDPRLPL
  QSSRPTSALVHRQHLTRQRSHSAGEVGEDSRHAGPPVLPRPSSTFNTVSRPQYQDMVPVA
  YNDKIVAFLRQPNIFEILQERQPDLTRNHSLREKIQFIRTEGTPGLVRLSSDADLVMLLS
  LFEEEIMSYVPPHALLHPSYCQSPRGSPVSSPQNSPGTQRANARAPAPYKRDFEAKLRNF
  YRKLETKGYGQGPGKLKLIIRRDHLLEDAFNQIMGYSRKDLQRNKLYVTFVGEEGLDYSG
  PSREFFFLVSRELFNPYYGLFEYSANDTYTVQISPMSAFVDNHHEWFRFSGRILGLALIH
  QYLLDAFFTRPFYKALLRILCDLSDLEYLDEEFHQSLQWMKDNDIHDILDLTFTVNEEVF
  GQITERELKPGGANIPVTEKNKKEYIERMVKWRIERGVVQQTESLVRGFYEVVDARLVSV
  FDARELELVIAGTAEIDLSDWRNNTEYRGGYHDNHIVIRWFWAAVERFNNEQRLRLLQFV
  TGTSSIPYEGFASLRGSNGPRRFCVEKWGKITALPRAHTCFNRLDLPPYPSFSMLYEKLL
  TAVEETSTFGLE
• Function: E3 ubiquitin-protein ligase that mediates ubiquitination of TP73. Acts to stabilize TP73 and enhance activation of transcription by TP73. Involved in the regulation of mitotic metaphase/anaphase transition.
• Tissue Specificity: Predominantly expressed in adult brain, lung and heart.
• Reactome Pathway: Antigen processing (R-HSA-983168)

Molecular Interaction Atlas (MIA) of This DOT

12 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Cervical cancer	DISFSHPF	Definitive	Altered Expression	[1]
Cervical carcinoma	DIST4S00	Definitive	Altered Expression	[1]
Colon cancer	DISVC52G	Definitive	Altered Expression	[1]
Colon carcinoma	DISJYKUO	Definitive	Altered Expression	[1]
Complex neurodevelopmental disorder	DISB9AFI	Definitive	Autosomal dominant	[2]
Neurodevelopmental disorder with hypotonia, seizures, and absent language	DIS3IT59	Definitive	Autosomal dominant	[3]
Alzheimer disease	DISF8S70	Strong	Biomarker	[4]
Epilepsy	DISBB28L	Strong	Biomarker	[5]
Intellectual disability	DISMBNXP	Strong	Genetic Variation	[6]
Neurodevelopmental disorder	DIS372XH	Strong	Genetic Variation	[7]
Emery-Dreifuss muscular dystrophy	DISYTPR5	Limited	Altered Expression	[8]
Schizophrenia	DISSRV2N	Limited	Genetic Variation	[9]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[10]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[11]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[12]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[14]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[15]
Vorinostat	DMWMPD4	Approved	Vorinostat decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[16]
Testosterone	DM7HUNW	Approved	Testosterone decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[15]
Melphalan	DMOLNHF	Approved	Melphalan decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[17]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of E3 ubiquitin-protein ligase HECW2 (HECW2).	[19]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of E3 ubiquitin-protein ligase HECW2 (HECW2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of E3 ubiquitin-protein ligase HECW2 (HECW2).	[20]

References

• [1] The HECT type ubiquitin ligase NEDL2 is degraded by anaphase-promoting complex/cyclosome (APC/C)-Cdh1, and its tight regulation maintains the metaphase to anaphase transition.J Biol Chem. 2013 Dec 13;288(50):35637-50. doi: 10.1074/jbc.M113.472076. Epub 2013 Oct 25.
• [2] Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med. 2020 Feb;22(2):245-257. doi: 10.1038/s41436-019-0686-8. Epub 2019 Nov 6.
• [3] Delineating the genotypic and phenotypic spectrum of HECW2-related neurodevelopmental disorders. J Med Genet. 2022 Jul;59(7):669-677. doi: 10.1136/jmedgenet-2021-107871. Epub 2021 Jul 28.
• [4] A genome-wide association study of aging.Neurobiol Aging. 2011 Nov;32(11):2109.e15-28. doi: 10.1016/j.neurobiolaging.2011.05.026. Epub 2011 Jul 22.
• [5] Mutations in HECW2 are associated with intellectual disability and epilepsy.J Med Genet. 2016 Oct;53(10):697-704. doi: 10.1136/jmedgenet-2016-103814. Epub 2016 Jun 22.
• [6] Rett-like features and cortical visual impairment in a Japanese patient with HECW2 mutation.Brain Dev. 2018 May;40(5):410-414. doi: 10.1016/j.braindev.2017.12.015. Epub 2018 Feb 1.
• [7] De novo missense variants in HECW2 are associated with neurodevelopmental delay and hypotonia. J Med Genet. 2017 Feb;54(2):84-86. doi: 10.1136/jmedgenet-2016-103943. Epub 2016 Jul 7.
• [8] E3 ubiquitin ligase HECW2 targets PCNA and lamin B1.Biochim Biophys Acta Mol Cell Res. 2018 Aug;1865(8):1088-1104. doi: 10.1016/j.bbamcr.2018.05.008. Epub 2018 May 17.
• [9] Genome-wide association study of schizophrenia in Ashkenazi Jews.Am J Med Genet B Neuropsychiatr Genet. 2015 Dec;168(8):649-59. doi: 10.1002/ajmg.b.32349. Epub 2015 Jul 21.
• [10] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [11] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [12] 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.
• [13] 17-Estradiol Activates HSF1 via MAPK Signaling in ER-Positive Breast Cancer Cells. Cancers (Basel). 2019 Oct 11;11(10):1533. doi: 10.3390/cancers11101533.
• [14] 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.
• [15] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [16] 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.
• [17] Bone marrow osteoblast damage by chemotherapeutic agents. PLoS One. 2012;7(2):e30758. doi: 10.1371/journal.pone.0030758. Epub 2012 Feb 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] 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.