Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIU02BS)

• DOT Name: Protein Daple (CCDC88C)
• Synonyms: Coiled-coil domain-containing protein 88C; Dvl-associating protein with a high frequency of leucine residues; hDaple; Hook-related protein 2; HkRP2
• Gene Name: CCDC88C
• Related Disease:
  Breast cancer
  Breast carcinoma
  Chronic eosinophilic leukemia
  Hydrocephalus, nonsyndromic, autosomal recessive 1
  Neoplasm
  Pituitary stalk interruption syndrome
  Schizophrenia
  Hydrocephalus
  Spinocerebellar ataxia type 40
  Cutaneous melanoma
  Melanoma
  Rheumatoid arthritis
  Congenital hydrocephalus
  Lymphoblastic lymphoma
  Myeloid neoplasm
  Myeloproliferative neoplasm
  Neurodevelopmental disorder
• UniProt ID: DAPLE_HUMAN
• Pfam ID: PF19047
• Sequence:
  MDVTVSELLELFLQSPLVTWVKTFGPFGSGSQDNLTMYMDLVDGIFLNQIMLQIDPRPTN
  QRINKHVNNDVNLRIQNLTILVRNIKTYYQEVLQQLIVMNLPNVLMIGRDPLSGKSMEEI
  KKVLLLVLGCAVQCERKEEFIERIKQLDIETQAGIVAHIQEVTHNQENVFDLQWLELPDV
  APEELEALSRSMVLHLRRLIDQRDECTELIVDLTQERDYLQAQHPPSPIKSSSADSTPSP
  TSSLSSEDKQHLAVELADTKARLRRVRQELEDKTEQLVDTRHEVDQLVLELQKVKQENIQ
  LAADARSARAYRDELDSLREKANRVERLELELTRCKEKLHDVDFYKARMEELREDNIILI
  ETKAMLEEQLTAARARGDKVHELEKENLQLKSKLHDLELDRDTDKKRIEELLEENMVLEI
  AQKQSMNESAHLGWELEQLSKNADLSDASRKSFVFELNECASSRILKLEKENQSLQSTIQ
  GLRDASLVLEESGLKCGELEKENHQLSKKIEKLQTQLEREKQSNQDLETLSEELIREKEQ
  LQSDMETLKADKARQIKDLEQEKDHLNRAMWSLRERSQVSSEARMKDVEKENKALHQTVT
  EANGKLSQLEFEKRQLHRDLEQAKEKGERAEKLERELQRLQEENGRLARKVTSLETATEK
  VEALEHESQGLQLENRTLRKSLDTLQNVSLQLEGLERDNKQLDAENLELRRLVETMRFTS
  TKLAQMERENQQLEREKEELRKNVDLLKALGKKSERLELSYQSVSAENLRLQQSLESSSH
  KTQTLESELGELEAERQALRRDLEALRLANAQLEGAEKDRKALEQEVAQLEKDKKLLEKE
  AKRLWQQVELKDAVLDDSTAKLSAVEKESRALDKELARCRDAAGKLKELEKDNRDLTKQV
  TVHARTLTTLREDLVLEKLKSQQLSSELDKLSQELEKVGLNRELLLQEDDSGSDTKYKIL
  EGRNESALKTTLAMKEEKIVLLEAQMEEKASLNRQLESELQMLKKECETLRQNQGEGQHL
  QNSFKHPAGKTAASHQGKEAWGPGHKEATMELLRVKDRAIELERNNAALQAEKQLLKEQL
  QHLETQNVTFSSQILTLQKQSAFLQEHNTTLQTQTAKLQVENSTLSSQSAALTAQYTLLQ
  NHHTAKETENESLQRQQEQLTAAYEALLQDHEHLGTLHERQSAEYEALIRQHSCLKTLHR
  NLELEHKELGERHGDMLKRKAELEEREKVLTTEREALQQEQRTNALAMGENQRLRGELDR
  VNFLHHQLKGEYEELHAHTKELKTSLNNAQLELNRWQARFDELKEQHQTMDISLTKLDNH
  CELLSRLKGNLEEENHHLLSQIQLLSQQNQMLLEQNMENKEQYHEEQKQYIDKLNALRRH
  KEKLEEKIMDQYKFYDPPPKKKNHWIGAKALVKLIKPKKEGSRERLKSTVDSPPWQLESS
  DPASPAASQPLRSQAENPDTPALGSNCAEERDAHNGSVGKGPGDLKPKRGSPHRGSLDRT
  DASTDLAMRSWPSELGSRTCSTSATTTAPSNSTPIARHPGRTKGYNSDDNLCEPSLEFEV
  PNHRQYVSRPSSLESSRNTSSNSSPLNLKGSSEQLHGRSESFSSEDLIPSRDLATLPREA
  STPGRNALGRHEYPLPRNGPLPQEGAQKRGTAPPYVGVRPCSASPSSEMVTLEEFLEESN
  RSSPTHDTPSCRDDLLSDYFRKASDPPAIGGQPGPPAKKEGAKMPTNFVAPTVKMAAPTS
  EGRPLKPGQYVKPNFRLTEAEAPPSVAPRQAQPPQSLSLGRPRQAPVPPASHAPASRSAS
  LSRAFSLASADLLRASGPEACKQESPQKLGAPEALGGRETGSHTLQSPAPPSSHSLARER
  TPLVGKAGSSCQGPGPRSRPLDTRRFSLAPPKEERLAPLHQSATAPAIATAGAGAAAAGS
  GSNSQLLHFSPAAAPAARTKPKAPPRSGEVATITPVRAGLSLSEGDGVPGQGCSEGLPAK
  SPGRSPDLAPHLGRALEDCSRGSVSKSSPASPEPGGDPQTVWYEYGCV
• Function: Required for activation of guanine nucleotide-binding proteins (G-proteins) during non-canonical Wnt signaling. Binds to ligand-activated Wnt receptor FZD7, displacing DVL1 from the FZD7 receptor and leading to inhibition of canonical Wnt signaling. Acts as a non-receptor guanine nucleotide exchange factor by also binding to guanine nucleotide-binding protein G(i) alpha (Gi-alpha) subunits, leading to their activation. Binding to Gi-alpha subunits displaces the beta and gamma subunits from the heterotrimeric G-protein complex, triggering non-canonical Wnt responses such as activation of RAC1 and PI3K-AKT signaling. Promotes apical constriction of cells via ARHGEF18.
• KEGG Pathway: Wnt sig.ling pathway (hsa04310)
• Reactome Pathway: Negative regulation of TCF-dependent signaling by DVL-interacting proteins (R-HSA-5368598)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Breast cancer	DIS7DPX1	Strong	Genetic Variation	[1]
Breast carcinoma	DIS2UE88	Strong	Genetic Variation	[2]
Chronic eosinophilic leukemia	DISAJOUO	Strong	Biomarker	[3]
Hydrocephalus, nonsyndromic, autosomal recessive 1	DISCYZI4	Strong	Autosomal recessive	[4]
Neoplasm	DISZKGEW	Strong	Biomarker	[5]
Pituitary stalk interruption syndrome	DISGSN5T	Strong	Biomarker	[6]
Schizophrenia	DISSRV2N	Strong	Genetic Variation	[7]
Hydrocephalus	DISIZUF7	moderate	Biomarker	[8]
Spinocerebellar ataxia type 40	DISYX3KE	Moderate	Autosomal dominant	[4]
Cutaneous melanoma	DIS3MMH9	Disputed	Biomarker	[9]
Melanoma	DIS1RRCY	Disputed	Biomarker	[9]
Rheumatoid arthritis	DISTSB4J	Disputed	Genetic Variation	[10]
Congenital hydrocephalus	DIS7O6UL	Limited	Genetic Variation	[8]
Lymphoblastic lymphoma	DISB9ZYC	Limited	Genetic Variation	[11]
Myeloid neoplasm	DIS2YOWO	Limited	Biomarker	[12]
Myeloproliferative neoplasm	DIS5KAPA	Limited	Genetic Variation	[11]
Neurodevelopmental disorder	DIS372XH	Limited	Biomarker	[13]

5 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 Protein Daple (CCDC88C).	[14]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Protein Daple (CCDC88C).	[19]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Protein Daple (CCDC88C).	[23]
PMID28870136-Compound-52	DMFDERP	Patented	PMID28870136-Compound-52 affects the phosphorylation of Protein Daple (CCDC88C).	[24]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Protein Daple (CCDC88C).	[25]

9 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 Protein Daple (CCDC88C).	[15]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Protein Daple (CCDC88C).	[16]
Cisplatin	DMRHGI9	Approved	Cisplatin decreases the expression of Protein Daple (CCDC88C).	[17]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Protein Daple (CCDC88C).	[18]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Protein Daple (CCDC88C).	[20]
Demecolcine	DMCZQGK	Approved	Demecolcine increases the expression of Protein Daple (CCDC88C).	[21]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Protein Daple (CCDC88C).	[22]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Protein Daple (CCDC88C).	[21]
Coumestrol	DM40TBU	Investigative	Coumestrol decreases the expression of Protein Daple (CCDC88C).	[26]

References

• [1] Evaluating genome-wide association study-identified breast cancer risk variants in African-American women.PLoS One. 2013 Apr 8;8(4):e58350. doi: 10.1371/journal.pone.0058350. Print 2013.
• [2] Association analysis identifies 65 new breast cancer risk loci.Nature. 2017 Nov 2;551(7678):92-94. doi: 10.1038/nature24284. Epub 2017 Oct 23.
• [3] Extramedullary molecular evidence of the 5'KIAA1509/3'PDGFRB fusion gene in chronic eosinophilic leukemia.Leuk Res. 2008 Feb;32(2):347-51. doi: 10.1016/j.leukres.2007.06.016. Epub 2007 Aug 2.
• [4] The Gene Curation Coalition: A global effort to harmonize gene-disease evidence resources. Genet Med. 2022 Aug;24(8):1732-1742. doi: 10.1016/j.gim.2022.04.017. Epub 2022 May 4.
• [5] Identification and functional characterization of imatinib-sensitive DTD1-PDGFRB and CCDC88C-PDGFRB fusion genes in eosinophilia-associated myeloid/lymphoid neoplasms.Genes Chromosomes Cancer. 2014 May;53(5):411-21. doi: 10.1002/gcc.22153.
• [6] Clues for Polygenic Inheritance of Pituitary Stalk Interruption Syndrome From Exome Sequencing in 20 Patients.J Clin Endocrinol Metab. 2018 Feb 1;103(2):415-428. doi: 10.1210/jc.2017-01660.
• [7] Common variants on 8p12 and 1q24.2 confer risk of schizophrenia.Nat Genet. 2011 Oct 30;43(12):1224-7. doi: 10.1038/ng.980.
• [8] Bi-allelic mutations of CCDC88C are a rare cause of severe congenital hydrocephalus.Am J Med Genet A. 2018 Mar;176(3):676-681. doi: 10.1002/ajmg.a.38592. Epub 2018 Jan 17.
• [9] Prognostic Relevance of CCDC88C (Daple) Transcripts in the Peripheral Blood of Patients with Cutaneous Melanoma.Sci Rep. 2018 Dec 21;8(1):18036. doi: 10.1038/s41598-018-36173-x.
• [10] Identification of pathogenic genes related to rheumatoid arthritis through integrated analysis of DNA methylation and gene expression profiling.Gene. 2017 Nov 15;634:62-67. doi: 10.1016/j.gene.2017.08.032. Epub 2017 Sep 4.
• [11] Sustained Response to Imatinib in a Pediatric Patient with Concurrent Myeloproliferative Disease and Lymphoblastic Lymphoma Associated with a CCDC88C-PDGFRB Fusion Gene.Acta Haematol. 2019;141(2):119-127. doi: 10.1159/000495687. Epub 2019 Feb 6.
• [12] A case of myeloid neoplasm associated with eosinophilia and KIAA1509-PDGFR responsive to combination treatment with imatinib mesylate and prednisolone.J Clin Pharm Ther. 2010 Dec;35(6):733-6. doi: 10.1111/j.1365-2710.2009.01130.x.
• [13] GPCR-independent activation of G proteins promotes apical cell constriction in vivo.J Cell Biol. 2019 May 6;218(5):1743-1763. doi: 10.1083/jcb.201811174. Epub 2019 Apr 4.
• [14] 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.
• [15] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [16] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [17] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [18] Genistein and bisphenol A exposure cause estrogen receptor 1 to bind thousands of sites in a cell type-specific manner. Genome Res. 2012 Nov;22(11):2153-62.
• [19] 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.
• [20] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [21] Characterization of formaldehyde's genotoxic mode of action by gene expression analysis in TK6 cells. Arch Toxicol. 2013 Nov;87(11):1999-2012.
• [22] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [23] 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.
• [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] 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.
• [26] Pleiotropic combinatorial transcriptomes of human breast cancer cells exposed to mixtures of dietary phytoestrogens. Food Chem Toxicol. 2009 Apr;47(4):787-95.