Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTDADBM4)

• DOT Name: CD109 antigen (CD109)
• Synonyms: 150 kDa TGF-beta-1-binding protein; C3 and PZP-like alpha-2-macroglobulin domain-containing protein 7; Platelet-specific Gov antigen; p180; r150; CD antigen CD109
• Gene Name: CD109
• Related Disease:
  Rheumatoid arthritis
  Adult glioblastoma
  Amyloidosis
  B-cell lymphoma
  Bone osteosarcoma
  Breast cancer
  Breast carcinoma
  Breast neoplasm
  Colonic neoplasm
  Colorectal carcinoma
  Dermatitis
  Glioma
  Haematological malignancy
  Hepatocellular carcinoma
  Lung squamous cell carcinoma
  Malignant glioma
  Marfan syndrome
  Multiple endocrine neoplasia
  Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4
  Myopathy
  Osteosarcoma
  Pancreatic adenocarcinoma
  Pancreatic cancer
  Squamous cell carcinoma
  Advanced cancer
  Carcinoma
  Endometrium adenocarcinoma
  Malignant soft tissue neoplasm
  Neoplasm
  Sarcoma
  Soft tissue sarcoma
  Colorectal neoplasm
  Lung cancer
  Lung carcinoma
  Glioblastoma multiforme
  Prostate cancer
  Prostate carcinoma
• UniProt ID: CD109_HUMAN
• Pfam ID: PF00207 ; PF07703 ; PF07677 ; PF01835 ; PF17791 ; PF07678
• Sequence:
  MQGPPLLTAAHLLCVCTAALAVAPGPRFLVTAPGIIRPGGNVTIGVELLEHCPSQVTVKA
  ELLKTASNLTVSVLEAEGVFEKGSFKTLTLPSLPLNSADEIYELRVTGRTQDEILFSNST
  RLSFETKRISVFIQTDKALYKPKQEVKFRIVTLFSDFKPYKTSLNILIKDPKSNLIQQWL
  SQQSDLGVISKTFQLSSHPILGDWSIQVQVNDQTYYQSFQVSEYVLPKFEVTLQTPLYCS
  MNSKHLNGTITAKYTYGKPVKGDVTLTFLPLSFWGKKKNITKTFKINGSANFSFNDEEMK
  NVMDSSNGLSEYLDLSSPGPVEILTTVTESVTGISRNVSTNVFFKQHDYIIEFFDYTTVL
  KPSLNFTATVKVTRADGNQLTLEERRNNVVITVTQRNYTEYWSGSNSGNQKMEAVQKINY
  TVPQSGTFKIEFPILEDSSELQLKAYFLGSKSSMAVHSLFKSPSKTYIQLKTRDENIKVG
  SPFELVVSGNKRLKELSYMVVSRGQLVAVGKQNSTMFSLTPENSWTPKACVIVYYIEDDG
  EIISDVLKIPVQLVFKNKIKLYWSKVKAEPSEKVSLRISVTQPDSIVGIVAVDKSVNLMN
  ASNDITMENVVHELELYNTGYYLGMFMNSFAVFQECGLWVLTDANLTKDYIDGVYDNAEY
  AERFMEENEGHIVDIHDFSLGSSPHVRKHFPETWIWLDTNMGYRIYQEFEVTVPDSITSW
  VATGFVISEDLGLGLTTTPVELQAFQPFFIFLNLPYSVIRGEEFALEITIFNYLKDATEV
  KVIIEKSDKFDILMTSNEINATGHQQTLLVPSEDGATVLFPIRPTHLGEIPITVTALSPT
  ASDAVTQMILVKAEGIEKSYSQSILLDLTDNRLQSTLKTLSFSFPPNTVTGSERVQITAI
  GDVLGPSINGLASLIRMPYGCGEQNMINFAPNIYILDYLTKKKQLTDNLKEKALSFMRQG
  YQRELLYQREDGSFSAFGNYDPSGSTWLSAFVLRCFLEADPYIDIDQNVLHRTYTWLKGH
  QKSNGEFWDPGRVIHSELQGGNKSPVTLTAYIVTSLLGYRKYQPNIDVQESIHFLESEFS
  RGISDNYTLALITYALSSVGSPKAKEALNMLTWRAEQEGGMQFWVSSESKLSDSWQPRSL
  DIEVAAYALLSHFLQFQTSEGIPIMRWLSRQRNSLGGFASTQDTTVALKALSEFAALMNT
  ERTNIQVTVTGPSSPSPVKFLIDTHNRLLLQTAELAVVQPTAVNISANGFGFAICQLNVV
  YNVKASGSSRRRRSIQNQEAFDLDVAVKENKDDLNHVDLNVCTSFSGPGRSGMALMEVNL
  LSGFMVPSEAISLSETVKKVEYDHGKLNLYLDSVNETQFCVNIPAVRNFKVSNTQDASVS
  IVDYYEPRRQAVRSYNSEVKLSSCDLCSDVQGCRPCEDGASGSHHHSSVIFIFCFKLLYF
  MELWL
• Function: Modulates negatively TGFB1 signaling in keratinocytes.
• Tissue Specificity: Widely expressed with high level in uterus, aorta, heart, lung, trachea, placenta and in fetal heart, kidney, liver, spleen and lung. Expressed by CD34(+) acute myeloid leukemia cell lines, T-cell lines, activated T-lymphoblasts, endothelial cells and activated platelets. Isoform 4 is expressed in placenta. Isoform 1 is expressed in keratinocytes and placenta.
• Reactome Pathway:
  Post-translational modification (R-HSA-163125)
  Platelet degranulation (R-HSA-114608)

Molecular Interaction Atlas (MIA) of This DOT

37 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[1]
Adult glioblastoma	DISVP4LU	Strong	Posttranslational Modification	[2]
Amyloidosis	DISHTAI2	Strong	Biomarker	[3]
B-cell lymphoma	DISIH1YQ	Strong	Biomarker	[4]
Bone osteosarcoma	DIST1004	Strong	Biomarker	[5]
Breast cancer	DIS7DPX1	Strong	Biomarker	[6]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[6]
Breast neoplasm	DISNGJLM	Strong	Biomarker	[6]
Colonic neoplasm	DISSZ04P	Strong	Genetic Variation	[7]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[8]
Dermatitis	DISY5SZC	Strong	Biomarker	[9]
Glioma	DIS5RPEH	Strong	Biomarker	[10]
Haematological malignancy	DISCDP7W	Strong	Biomarker	[4]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[11]
Lung squamous cell carcinoma	DISXPIBD	Strong	Altered Expression	[12]
Malignant glioma	DISFXKOV	Strong	Biomarker	[10]
Marfan syndrome	DISVEUWZ	Strong	Altered Expression	[13]
Multiple endocrine neoplasia	DISZGBKW	Strong	Altered Expression	[14]
Muscular dystrophy-dystroglycanopathy (congenital with brain and eye anomalies), type A, 4	DISGM0K5	Strong	Biomarker	[15]
Myopathy	DISOWG27	Strong	Biomarker	[15]
Osteosarcoma	DISLQ7E2	Strong	Biomarker	[5]
Pancreatic adenocarcinoma	DISKHX7S	Strong	Altered Expression	[16]
Pancreatic cancer	DISJC981	Strong	Altered Expression	[16]
Squamous cell carcinoma	DISQVIFL	Strong	Altered Expression	[17]
Advanced cancer	DISAT1Z9	moderate	Altered Expression	[16]
Carcinoma	DISH9F1N	moderate	Biomarker	[18]
Endometrium adenocarcinoma	DISY6744	moderate	Altered Expression	[19]
Malignant soft tissue neoplasm	DISTC6NO	moderate	Biomarker	[20]
Neoplasm	DISZKGEW	moderate	Biomarker	[21]
Sarcoma	DISZDG3U	moderate	Biomarker	[20]
Soft tissue sarcoma	DISSN8XB	moderate	Altered Expression	[20]
Colorectal neoplasm	DISR1UCN	Disputed	Biomarker	[8]
Lung cancer	DISCM4YA	Disputed	Biomarker	[22]
Lung carcinoma	DISTR26C	Disputed	Biomarker	[22]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[21]
Prostate cancer	DISF190Y	Limited	Biomarker	[23]
Prostate carcinoma	DISMJPLE	Limited	Biomarker	[23]

17 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 CD109 antigen (CD109).	[24]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of CD109 antigen (CD109).	[25]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of CD109 antigen (CD109).	[26]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of CD109 antigen (CD109).	[27]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of CD109 antigen (CD109).	[28]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of CD109 antigen (CD109).	[29]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of CD109 antigen (CD109).	[31]
Temozolomide	DMKECZD	Approved	Temozolomide decreases the expression of CD109 antigen (CD109).	[32]
Cannabidiol	DM0659E	Approved	Cannabidiol decreases the expression of CD109 antigen (CD109).	[33]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of CD109 antigen (CD109).	[34]
DNCB	DMDTVYC	Phase 2	DNCB increases the expression of CD109 antigen (CD109).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of CD109 antigen (CD109).	[36]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of CD109 antigen (CD109).	[37]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of CD109 antigen (CD109).	[38]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of CD109 antigen (CD109).	[39]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of CD109 antigen (CD109).	[40]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride increases the expression of CD109 antigen (CD109).	[35]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of CD109 antigen (CD109).	[30]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of CD109 antigen (CD109).	[41]

References

• [1] CD109 regulates the inflammatory response and is required for the pathogenesis of rheumatoid arthritis.Ann Rheum Dis. 2019 Dec;78(12):1632-1641. doi: 10.1136/annrheumdis-2019-215473. Epub 2019 Aug 27.
• [2] CD109 attenuates TGF-1 signaling and enhances EGF signaling in SK-MG-1 human glioblastoma cells.Biochem Biophys Res Commun. 2015 Apr 3;459(2):252-258. doi: 10.1016/j.bbrc.2015.02.093. Epub 2015 Feb 25.
• [3] Higher levels of kallikrein-8 in female brain may increase the risk for Alzheimer's disease.Brain Pathol. 2018 Nov;28(6):947-964. doi: 10.1111/bpa.12599. Epub 2018 Apr 10.
• [4] CD109, a negative regulator of TGF- signaling, is a putative risk marker in diffuse large B-cell lymphoma.Int J Hematol. 2017 May;105(5):614-622. doi: 10.1007/s12185-016-2173-1. Epub 2016 Dec 28.
• [5] p180, a novel recycling transmembrane glycoprotein with restricted cell type expression.Mol Cell Biol. 1990 Jun;10(6):2606-18. doi: 10.1128/mcb.10.6.2606-2618.1990.
• [6] Convergence of mutation and epigenetic alterations identifies common genes in cancer that predict for poor prognosis.PLoS Med. 2008 May 27;5(5):e114. doi: 10.1371/journal.pmed.0050114.
• [7] The consensus coding sequences of human breast and colorectal cancers.Science. 2006 Oct 13;314(5797):268-74. doi: 10.1126/science.1133427. Epub 2006 Sep 7.
• [8] Genomic and epigenomic integration identifies a prognostic signature in colon cancer.Clin Cancer Res. 2011 Mar 15;17(6):1535-45. doi: 10.1158/1078-0432.CCR-10-2509. Epub 2011 Jan 28.
• [9] CD109 deficiency induces osteopenia with an osteoporosis-like phenotype in vivo.Genes Cells. 2018 Jul;23(7):590-598. doi: 10.1111/gtc.12593. Epub 2018 May 16.
• [10] Revealing the glioma cancer stem cell interactome, one niche at a time.J Pathol. 2018 Mar;244(3):260-264. doi: 10.1002/path.5024. Epub 2018 Feb 2.
• [11] CD109 Mediates Cell Survival in Hepatocellular Carcinoma Cells.Dig Dis Sci. 2016 Aug;61(8):2303-2314. doi: 10.1007/s10620-016-4149-7. Epub 2016 Apr 13.
• [12] CD109 expression is upregulated in penile squamous cell carcinoma.Oncol Lett. 2017 Nov;14(5):6012-6016. doi: 10.3892/ol.2017.6975. Epub 2017 Sep 15.
• [13] Characterization and Drug Sensitivity of a New High-Grade Myxofibrosarcoma Cell Line.Cells. 2018 Oct 25;7(11):186. doi: 10.3390/cells7110186.
• [14] Expression of CD109 in human cancer.Oncogene. 2004 Apr 29;23(20):3716-20. doi: 10.1038/sj.onc.1207418.
• [15] Deficiency of a 180-kDa extracellular matrix protein in Fukuyama type congenital muscular dystrophy skeletal muscle.Neuromuscul Disord. 2002 Feb;12(2):117-20. doi: 10.1016/s0960-8966(01)00251-6.
• [16] Development of novel monoclonal antibodies against CD109 overexpressed in human pancreatic cancer.Oncotarget. 2018 Apr 13;9(28):19994-20007. doi: 10.18632/oncotarget.25017. eCollection 2018 Apr 13.
• [17] CD109 acts as a gatekeeper of the epithelial trait by suppressing epithelial to mesenchymal transition in squamous cell carcinoma cells in vitro.Sci Rep. 2019 Nov 6;9(1):16317. doi: 10.1038/s41598-019-50694-z.
• [18] CD109, a new marker for myoepithelial cells of mammary, salivary, and lacrimal glands and prostate basal cells.Pathol Int. 2007 May;57(5):245-50. doi: 10.1111/j.1440-1827.2007.02097.x.
• [19] CD109 expression in squamous cell carcinoma of the uterine cervix.Pathol Int. 2005 Apr;55(4):165-9. doi: 10.1111/j.1440-1827.2005.01807.x.
• [20] High expression of CD109 antigen regulates the phenotype of cancer stem-like cells/cancer-initiating cells in the novel epithelioid sarcoma cell line ESX and is related to poor prognosis of soft tissue sarcoma.PLoS One. 2013 Dec 20;8(12):e84187. doi: 10.1371/journal.pone.0084187. eCollection 2013.
• [21] Phenotypic Plasticity of Invasive Edge Glioma Stem-like Cells in Response to Ionizing Radiation.Cell Rep. 2019 Feb 12;26(7):1893-1905.e7. doi: 10.1016/j.celrep.2019.01.076.
• [22] Molecular definition of a metastatic lung cancer state reveals a targetable CD109-Janus kinase-Stat axis.Nat Med. 2017 Mar;23(3):291-300. doi: 10.1038/nm.4285. Epub 2017 Feb 13.
• [23] Pre-diagnostic metabolite concentrations and prostate cancer risk in 1077 cases and 1077 matched controls in the European Prospective Investigation into Cancer and Nutrition.BMC Med. 2017 Jul 5;15(1):122. doi: 10.1186/s12916-017-0885-6.
• [24] 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.
• [25] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [26] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [27] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [28] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [29] 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.
• [30] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [31] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [32] 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.
• [33] Cannabidiol Modulates the Immunophenotype and Inhibits the Activation of the Inflammasome in Human Gingival Mesenchymal Stem Cells. Front Physiol. 2016 Nov 24;7:559. doi: 10.3389/fphys.2016.00559. eCollection 2016.
• [34] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [35] Preliminary discovery of novel markers for human cell line activation test (h-CLAT). Toxicol In Vitro. 2021 Aug;74:105154. doi: 10.1016/j.tiv.2021.105154. Epub 2021 Mar 25.
• [36] 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.
• [37] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [38] Bisphenol A induces DSB-ATM-p53 signaling leading to cell cycle arrest, senescence, autophagy, stress response, and estrogen release in human fetal lung fibroblasts. Arch Toxicol. 2018 Apr;92(4):1453-1469.
• [39] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.
• [40] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [41] 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.