Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT97FRYE)

• DOT Name: COP9 signalosome complex subunit 1 (GPS1)
• Synonyms: SGN1; Signalosome subunit 1; G protein pathway suppressor 1; GPS-1; JAB1-containing signalosome subunit 1; Protein MFH
• Gene Name: GPS1
• Related Disease:
  Gray platelet syndrome
  Neoplasm
  Penile cancer
  Schizophrenia
  Triple negative breast cancer
  Influenza
• UniProt ID: CSN1_HUMAN
• PDB ID: 4D10; 4D18; 4WSN; 6R6H; 6R7F; 6R7H; 6R7I; 6R7N; 8H38; 8H3A; 8H3F
• Pfam ID: PF21151 ; PF01399 ; PF10602
• Sequence:
  MPLPVQVFNLQGAVEPMQIDVDPQEDPQNAPDVNYVVENPSLDLEQYAASYSGLMRIERL
  QFIADHCPTLRVEALKMALSFVQRTFNVDMYEEIHRKLSEATRSSLRELQNAPDAIPESG
  VEPPALDTAWVEATRKKALLKLEKLDTDLKNYKGNSIKESIRRGHDDLGDHYLDCGDLSN
  ALKCYSRARDYCTSAKHVINMCLNVIKVSVYLQNWSHVLSYVSKAESTPEIAEQRGERDS
  QTQAILTKLKCAAGLAELAARKYKQAAKCLLLASFDHCDFPELLSPSNVAIYGGLCALAT
  FDRQELQRNVISSSSFKLFLELEPQVRDIIFKFYESKYASCLKMLDEMKDNLLLDMYLAP
  HVRTLYTQIRNRALIQYFSPYVSADMHRMAAAFNTTVAALEDELTQLILEGLISARVDSH
  SKILYARDVDQRSTTFEKSLLMGKEFQRRAKAMMLRAAVLRNQIHVKSPPREGSQGELTP
  ANSQSRMSTNM
• 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. Suppresses G-protein- and mitogen-activated protein kinase-mediated signal transduction.
• Tissue Specificity: Widely expressed.
• 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

6 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Gray platelet syndrome	DISLOTCW	Strong	Biomarker	[1]
Neoplasm	DISZKGEW	Strong	Genetic Variation	[2]
Penile cancer	DISGVGNQ	Strong	Genetic Variation	[2]
Schizophrenia	DISSRV2N	Strong	Biomarker	[3]
Triple negative breast cancer	DISAMG6N	Strong	Biomarker	[4]
Influenza	DIS3PNU3	moderate	Biomarker	[5]

3 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 COP9 signalosome complex subunit 1 (GPS1).	[6]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of COP9 signalosome complex subunit 1 (GPS1).	[11]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 decreases the phosphorylation of COP9 signalosome complex subunit 1 (GPS1).	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Doxorubicin	DMVP5YE	Approved	Doxorubicin increases the expression of COP9 signalosome complex subunit 1 (GPS1).	[7]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of COP9 signalosome complex subunit 1 (GPS1).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of COP9 signalosome complex subunit 1 (GPS1).	[9]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of COP9 signalosome complex subunit 1 (GPS1).	[10]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of COP9 signalosome complex subunit 1 (GPS1).	[12]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of COP9 signalosome complex subunit 1 (GPS1).	[14]

References

• [1] Glasgow prognostic score predicts therapeutic outcome after hepatic resection for hepatocellular carcinoma.Oncol Lett. 2017 Jul;14(1):293-298. doi: 10.3892/ol.2017.6104. Epub 2017 Apr 28.
• [2] CSN1 Somatic Mutations in Penile Squamous Cell Carcinoma.Cancer Res. 2016 Aug 15;76(16):4720-4727. doi: 10.1158/0008-5472.CAN-15-3134. Epub 2016 Jun 20.
• [3] Abnormal expression of glutamate transporter and transporter interacting molecules in prefrontal cortex in elderly patients with schizophrenia.Schizophr Res. 2008 Sep;104(1-3):108-20. doi: 10.1016/j.schres.2008.06.012. Epub 2008 Aug 3.
• [4] The transcriptional coactivator WBP2 primes triple-negative breast cancer cells for responses to Wnt signaling via the JNK/Jun kinase pathway.J Biol Chem. 2018 Dec 28;293(52):20014-20028. doi: 10.1074/jbc.RA118.005796. Epub 2018 Nov 15.
• [5] G Protein Pathway Suppressor 1 Promotes Influenza Virus Polymerase Activity by Activating the NF-B Signaling Pathway.mBio. 2019 Dec 17;10(6):e02867-19. doi: 10.1128/mBio.02867-19.
• [6] 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.
• [7] 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.
• [8] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [9] 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.
• [10] Quantitative proteomics and transcriptomics addressing the estrogen receptor subtype-mediated effects in T47D breast cancer cells exposed to the phytoestrogen genistein. Mol Cell Proteomics. 2011 Jan;10(1):M110.002170.
• [11] 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.
• [12] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [13] 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.
• [14] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.