Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT82JIGC)

• DOT Name: Coatomer subunit beta' (COPB2)
• Synonyms: Beta'-coat protein; Beta'-COP; p102
• Gene Name: COPB2
• Related Disease:
  Advanced cancer
  Arteriosclerosis
  Atherosclerosis
  Cholangiocarcinoma
  Cytomegalovirus infection
  Diabetic kidney disease
  Gastric cancer
  Glomerulosclerosis
  Isolated congenital microcephaly
  Lung adenocarcinoma
  Malignant soft tissue neoplasm
  Osteoporosis, childhood- or juvenile-onset, with developmental delay
  Prostate cancer
  Prostate carcinoma
  Sarcoma
  Scleroderma
  Scrub typhus
  Stomach cancer
  Systemic sclerosis
  Colorectal carcinoma
  Autosomal recessive primary microcephaly
  Microcephaly 19, primary, autosomal recessive
  Neoplasm
• UniProt ID: COPB2_HUMAN
• PDB ID: 8D30; 8D41
• Pfam ID: PF04053 ; PF00400
• Sequence:
  MPLRLDIKRKLTARSDRVKSVDLHPTEPWMLASLYNGSVCVWNHETQTLVKTFEVCDLPV
  RAAKFVARKNWVVTGADDMQIRVFNYNTLERVHMFEAHSDYIRCIAVHPTQPFILTSSDD
  MLIKLWDWDKKWSCSQVFEGHTHYVMQIVINPKDNNQFASASLDRTIKVWQLGSSSPNFT
  LEGHEKGVNCIDYYSGGDKPYLISGADDRLVKIWDYQNKTCVQTLEGHAQNVSCASFHPE
  LPIIITGSEDGTVRIWHSSTYRLESTLNYGMERVWCVASLRGSNNVALGYDEGSIIVKLG
  REEPAMSMDANGKIIWAKHSEVQQANLKAMGDAEIKDGERLPLAVKDMGSCEIYPQTIQH
  NPNGRFVVVCGDGEYIIYTAMALRNKSFGSAQEFAWAHDSSEYAIRESNSIVKIFKNFKE
  KKSFKPDFGAESIYGGFLLGVRSVNGLAFYDWDNTELIRRIEIQPKHIFWSDSGELVCIA
  TEESFFILKYLSEKVLAAQETHEGVTEDGIEDAFEVLGEIQEIVKTGLWVGDCFIYTSSV
  NRLNYYVGGEIVTIAHLDRTMYLLGYIPKDNRLYLGDKELNIISYSLLVSVLEYQTAVMR
  RDFSMADKVLPTIPKEQRTRVAHFLEKQGFKQQALTVSTDPEHRFELALQLGELKIAYQL
  AVEAESEQKWKQLAELAISKCQFGLAQECLHHAQDYGGLLLLATASGNANMVNKLAEGAE
  RDGKNNVAFMSYFLQGKVDACLELLIRTGRLPEAAFLARTYLPSQVSRVVKLWRENLSKV
  NQKAAESLADPTEYENLFPGLKEAFVVEEWVKETHADLWPAKQYPLVTPNEERNVMEEGK
  DFQPSRSTAQQELDGKPASPTPVIVASHTANKEEKSLLELEVDLDNLELEDIDTTDINLD
  EDILDD
• Function: The coatomer is a cytosolic protein complex that binds to dilysine motifs and reversibly associates with Golgi non-clathrin-coated vesicles, which further mediate biosynthetic protein transport from the ER, via the Golgi up to the trans Golgi network. Coatomer complex is required for budding from Golgi membranes, and is essential for the retrograde Golgi-to-ER transport of dilysine-tagged proteins. In mammals, the coatomer can only be recruited by membranes associated to ADP-ribosylation factors (ARFs), which are small GTP-binding proteins; the complex also influences the Golgi structural integrity, as well as the processing, activity, and endocytic recycling of LDL receptors; This coatomer complex protein, essential for Golgi budding and vesicular trafficking, is a selective binding protein (RACK) for protein kinase C, epsilon type. It binds to Golgi membranes in a GTP-dependent manner.
• Reactome Pathway:
  COPI-dependent Golgi-to-ER retrograde traffic (R-HSA-6811434)
  COPI-mediated anterograde transport (R-HSA-6807878)

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[1]
Arteriosclerosis	DISK5QGC	Strong	Genetic Variation	[2]
Atherosclerosis	DISMN9J3	Strong	Genetic Variation	[2]
Cholangiocarcinoma	DIS71F6X	Strong	Altered Expression	[3]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[4]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[5]
Gastric cancer	DISXGOUK	Strong	Biomarker	[1]
Glomerulosclerosis	DISJF20Z	Strong	Biomarker	[5]
Isolated congenital microcephaly	DISUXHZ6	Strong	Genetic Variation	[6]
Lung adenocarcinoma	DISD51WR	Strong	Altered Expression	[7]
Malignant soft tissue neoplasm	DISTC6NO	Strong	Biomarker	[8]
Osteoporosis, childhood- or juvenile-onset, with developmental delay	DISI6LCA	Strong	Autosomal dominant	[9]
Prostate cancer	DISF190Y	Strong	Biomarker	[10]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[10]
Sarcoma	DISZDG3U	Strong	Biomarker	[8]
Scleroderma	DISVQ342	Strong	Biomarker	[11]
Scrub typhus	DISRXONX	Strong	Biomarker	[12]
Stomach cancer	DISKIJSX	Strong	Biomarker	[1]
Systemic sclerosis	DISF44L6	Strong	Biomarker	[11]
Colorectal carcinoma	DIS5PYL0	moderate	Altered Expression	[13]
Autosomal recessive primary microcephaly	DIS29IE3	Supportive	Autosomal recessive	[6]
Microcephaly 19, primary, autosomal recessive	DIS9R2ZC	Limited	Unknown	[14]
Neoplasm	DISZKGEW	Limited	Altered Expression	[1]

13 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 Coatomer subunit beta' (COPB2).	[15]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Coatomer subunit beta' (COPB2).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Coatomer subunit beta' (COPB2).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Coatomer subunit beta' (COPB2).	[18]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Coatomer subunit beta' (COPB2).	[19]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Coatomer subunit beta' (COPB2).	[20]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Coatomer subunit beta' (COPB2).	[21]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Coatomer subunit beta' (COPB2).	[22]
Fulvestrant	DM0YZC6	Approved	Fulvestrant decreases the expression of Coatomer subunit beta' (COPB2).	[18]
Bicalutamide	DMZMSPF	Approved	Bicalutamide increases the expression of Coatomer subunit beta' (COPB2).	[23]
Afimoxifene	DMFORDT	Phase 2	Afimoxifene decreases the expression of Coatomer subunit beta' (COPB2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Coatomer subunit beta' (COPB2).	[25]
Milchsaure	DM462BT	Investigative	Milchsaure decreases the expression of Coatomer subunit beta' (COPB2).	[26]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 increases the phosphorylation of Coatomer subunit beta' (COPB2).	[24]

References

• [1] Silencing of COPB2 inhibits the proliferation of gastric cancer cells and induces apoptosis via suppression of the RTK signaling pathway.Int J Oncol. 2019 Apr;54(4):1195-1208. doi: 10.3892/ijo.2019.4717. Epub 2019 Feb 18.
• [2] Atheroprotective vaccination with MHC-II-restricted ApoB peptides induces peritoneal IL-10-producing CD4 T cells.Am J Physiol Heart Circ Physiol. 2017 Apr 1;312(4):H781-H790. doi: 10.1152/ajpheart.00798.2016. Epub 2017 Jan 13.
• [3] Downregulation of COPB2 by RNAi inhibits growth of human cholangiocellular carcinoma cells.Eur Rev Med Pharmacol Sci. 2018 Feb;22(4):985-992. doi: 10.26355/eurrev_201802_14380.
• [4] Identification of Host Factors Involved in Human Cytomegalovirus Replication, Assembly, and Egress Using a Two-Step Small Interfering RNA Screen.mBio. 2018 Jun 26;9(3):e00716-18. doi: 10.1128/mBio.00716-18.
• [5] SND p102 promotes extracellular matrix accumulation and cell proliferation in rat glomerular mesangial cells via the AT1R/ERK/Smad3 pathway.Acta Pharmacol Sin. 2018 Sep;39(9):1513-1521. doi: 10.1038/aps.2017.184. Epub 2018 May 10.
• [6] Copb2 is essential for embryogenesis and hypomorphic mutations cause human microcephaly. Hum Mol Genet. 2017 Dec 15;26(24):4836-4848. doi: 10.1093/hmg/ddx362.
• [7] COPB2 promotes cell proliferation and tumorigenesis through up-regulating YAP1 expression in lung adenocarcinoma cells.Biomed Pharmacother. 2018 Jul;103:373-380. doi: 10.1016/j.biopha.2018.04.006. Epub 2018 Apr 24.
• [8] Engineering and characterization of a single-chain antibody fragment (scFV1924) against the human sarcoma-associated antigen p102.Anticancer Res. 2000 Jul-Aug;20(4):2753-60.
• [9] COPB2 loss of function causes a coatopathy with osteoporosis and developmental delay. Am J Hum Genet. 2021 Sep 2;108(9):1710-1724. doi: 10.1016/j.ajhg.2021.08.002. Epub 2021 Aug 26.
• [10] Coatomer subunit beta 2 (COPB2), identified by label-free quantitative proteomics, regulates cell proliferation and apoptosis in human prostate carcinoma cells.Biochem Biophys Res Commun. 2018 Jan 1;495(1):473-480. doi: 10.1016/j.bbrc.2017.11.040. Epub 2017 Nov 10.
• [11] Identification of the mouse beta'-COP Golgi component as a spermatocyte autoantigen in scleroderma and mapping of its gene Copb2 to mouse chromosome 9.Cytogenet Cell Genet. 1999;87(3-4):201-4. doi: 10.1159/000015467.
• [12] Orientia tsutsugamushi Ank9 is a multifunctional effector that utilizes a novel GRIP-like Golgi localization domain for Golgi-to-endoplasmic reticulum trafficking and interacts with host COPB2.Cell Microbiol. 2017 Jul;19(7):10.1111/cmi.12727. doi: 10.1111/cmi.12727. Epub 2017 Feb 3.
• [13] MicroRNA-4461 derived from bone marrow mesenchymal stem cell exosomes inhibits tumorigenesis by downregulating COPB2 expression in colorectal cancer.Biosci Biotechnol Biochem. 2020 Feb;84(2):338-346. doi: 10.1080/09168451.2019.1677452. Epub 2019 Oct 21.
• [14] Closing in on the BPES gene on 3q23: mapping of a de Novo reciprocal translocation t(3;4)(q23;p15.2) breakpoint within a 45-kb cosmid and mapping of three candidate genes, RBP1, RBP2, and beta'-COP, distal to the breakpoint. Genomics. 1999 Apr 1;57(1):70-8. doi: 10.1006/geno.1999.5747.
• [15] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [16] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [17] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [18] Comparative gene expression profiling reveals partially overlapping but distinct genomic actions of different antiestrogens in human breast cancer cells. J Cell Biochem. 2006 Aug 1;98(5):1163-84.
• [19] 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.
• [20] Proteomics-based identification of differentially abundant proteins from human keratinocytes exposed to arsenic trioxide. J Proteomics Bioinform. 2014 Jul;7(7):166-178.
• [21] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [22] JunD is involved in the antiproliferative effect of Delta9-tetrahydrocannabinol on human breast cancer cells. Oncogene. 2008 Aug 28;27(37):5033-44.
• [23] Differentially expressed genes in the prostate cancer cell line LNCaP after exposure to androgen and anti-androgen. Cancer Genet Cytogenet. 2006 Apr 15;166(2):130-8. doi: 10.1016/j.cancergencyto.2005.09.012.
• [24] 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.
• [25] Alternatives for the worse: Molecular insights into adverse effects of bisphenol a and substitutes during human adipocyte differentiation. Environ Int. 2021 Nov;156:106730. doi: 10.1016/j.envint.2021.106730. Epub 2021 Jun 27.
• [26] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.