Details of Drug Off-Target (DOT)

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

• DOT Name: COP9 signalosome complex subunit 2 (COPS2)
• Synonyms: SGN2; Signalosome subunit 2; Alien homolog; JAB1-containing signalosome subunit 2; Thyroid receptor-interacting protein 15; TR-interacting protein 15; TRIP-15
• Gene Name: COPS2
• Related Disease:
  Angelman syndrome
  Endometriosis
  Colorectal carcinoma
  Breast cancer
  Breast carcinoma
• UniProt ID: CSN2_HUMAN
• PDB ID: 4D10; 4D18; 4WSN; 6A73; 6R6H; 6R7F; 6R7H; 6R7I; 6R7N; 8H38; 8H3A; 8H3F
• Pfam ID: PF01399
• Sequence:
  MSDMEDDFMCDDEEDYDLEYSEDSNSEPNVDLENQYYNSKALKEDDPKAALSSFQKVLEL
  EGEKGEWGFKALKQMIKINFKLTNFPEMMNRYKQLLTYIRSAVTRNYSEKSINSILDYIS
  TSKQMDLLQEFYETTLEALKDAKNDRLWFKTNTKLGKLYLEREEYGKLQKILRQLHQSCQ
  TDDGEDDLKKGTQLLEIYALEIQMYTAQKNNKKLKALYEQSLHIKSAIPHPLIMGVIREC
  GGKMHLREGEFEKAHTDFFEAFKNYDESGSPRRTTCLKYLVLANMLMKSGINPFDSQEAK
  PYKNDPEILAMTNLVSAYQNNDITEFEKILKTNHSNIMDDPFIREHIEELLRNIRTQVLI
  KLIKPYTRIHIPFISKELNIDVADVESLLVQCILDNTIHGRIDQVNQLLELDHQKRGGAR
  YTALDKWTNQLNSLNQAVVSKLA
• Function: Essential component of the COP9 signalosome complex (CSN), a complex involved in various cellular and developmental processes. The CSN complex is an essential regulator of the ubiquitin (Ubl) conjugation pathway by mediating the deneddylation of the cullin subunits of SCF-type E3 ligase complexes, leading to decrease the Ubl ligase activity of SCF-type complexes such as SCF, CSA or DDB2. The complex is also involved in phosphorylation of p53/TP53, c-jun/JUN, IkappaBalpha/NFKBIA, ITPK1 and IRF8/ICSBP, possibly via its association with CK2 and PKD kinases. CSN-dependent phosphorylation of TP53 and JUN promotes and protects degradation by the Ubl system, respectively. Involved in early stage of neuronal differentiation via its interaction with NIF3L1.
• Reactome Pathway:
  Formation of TC-NER Pre-Incision Complex (R-HSA-6781823)
  Cargo recognition for clathrin-mediated endocytosis (R-HSA-8856825)
  Neddylation (R-HSA-8951664)
  RHOBTB1 GTPase cycle (R-HSA-9013422)
  DNA Damage Recognition in GG-NER (R-HSA-5696394)

Molecular Interaction Atlas (MIA) of This DOT

5 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Angelman syndrome	DIS4QVXO	Definitive	Biomarker	[1]
Endometriosis	DISX1AG8	Strong	Biomarker	[2]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[3]
Breast cancer	DIS7DPX1	Limited	Genetic Variation	[4]
Breast carcinoma	DIS2UE88	Limited	Genetic Variation	[4]

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 COP9 signalosome complex subunit 2 (COPS2).	[5]

8 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 COP9 signalosome complex subunit 2 (COPS2).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of COP9 signalosome complex subunit 2 (COPS2).	[7]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of COP9 signalosome complex subunit 2 (COPS2).	[8]
Phenobarbital	DMXZOCG	Approved	Phenobarbital affects the expression of COP9 signalosome complex subunit 2 (COPS2).	[9]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of COP9 signalosome complex subunit 2 (COPS2).	[10]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of COP9 signalosome complex subunit 2 (COPS2).	[11]
KOJIC ACID	DMP84CS	Investigative	KOJIC ACID decreases the expression of COP9 signalosome complex subunit 2 (COPS2).	[12]
Taurine	DMVW7N3	Investigative	Taurine increases the expression of COP9 signalosome complex subunit 2 (COPS2).	[13]

References

• [1] Molecular characterisation of four cases of intrachromosomal triplication of chromosome 15q11-q14.J Med Genet. 2001 Jan;38(1):26-34. doi: 10.1136/jmg.38.1.26.
• [2] Nuclear receptor, coregulator signaling, and chromatin remodeling pathways suggest involvement of the epigenome in the steroid hormone response of endometrium and abnormalities in endometriosis.Reprod Sci. 2012 Feb;19(2):152-62. doi: 10.1177/1933719111415546. Epub 2011 Dec 2.
• [3] Prognostic Significance of CSN2, CD8, and MMR Status-Associated Nomograms in Patients with Colorectal Cancer.Transl Oncol. 2018 Oct;11(5):1202-1212. doi: 10.1016/j.tranon.2018.07.006. Epub 2018 Jul 31.
• [4] Genetic variants of genes in the NER pathway associated with risk of breast cancer: A large-scale analysis of 14 published GWAS datasets in the DRIVE study.Int J Cancer. 2019 Sep 1;145(5):1270-1279. doi: 10.1002/ijc.32371. Epub 2019 May 13.
• [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] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [7] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] Reproducible chemical-induced changes in gene expression profiles in human hepatoma HepaRG cells under various experimental conditions. Toxicol In Vitro. 2009 Apr;23(3):466-75. doi: 10.1016/j.tiv.2008.12.018. Epub 2008 Dec 30.
• [10] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [11] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.
• [12] Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.
• [13] Taurine-responsive genes related to signal transduction as identified by cDNA microarray analyses of HepG2 cells. J Med Food. 2006 Spring;9(1):33-41. doi: 10.1089/jmf.2006.9.33.