Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ9IRFL)

DOT Name Frizzled-8 (FZD8)
Synonyms Fz-8; hFz8
Gene Name FZD8
Related Disease
Advanced cancer ( )
Chronic bronchitis ( )
Clear cell renal carcinoma ( )
Colorectal carcinoma ( )
Gastric cancer ( )
Interstitial cystitis ( )
Lung cancer ( )
Lung carcinoma ( )
Metastatic malignant neoplasm ( )
Neoplasm ( )
Non-small-cell lung cancer ( )
Psoriasis ( )
Renal cell carcinoma ( )
Stomach cancer ( )
Triple negative breast cancer ( )
Prostate cancer ( )
Prostate carcinoma ( )
Bone osteosarcoma ( )
Osteosarcoma ( )
Thyroid cancer ( )
Thyroid gland carcinoma ( )
Thyroid tumor ( )
UniProt ID
FZD8_HUMAN
3D Structure
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2D Sequence (FASTA)
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3D Structure (PDB)
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PDB ID
5UN5; 5UN6; 6NDZ; 8X0T
Pfam ID
PF01534 ; PF01392
Sequence
MEWGYLLEVTSLLAALALLQRSSGAAAASAKELACQEITVPLCKGIGYNYTYMPNQFNHD
TQDEAGLEVHQFWPLVEIQCSPDLKFFLCSMYTPICLEDYKKPLPPCRSVCERAKAGCAP
LMRQYGFAWPDRMRCDRLPEQGNPDTLCMDYNRTDLTTAAPSPPRRLPPPPPGEQPPSGS
GHGRPPGARPPHRGGGRGGGGGDAAAPPARGGGGGGKARPPGGGAAPCEPGCQCRAPMVS
VSSERHPLYNRVKTGQIANCALPCHNPFFSQDERAFTVFWIGLWSVLCFVSTFATVSTFL
IDMERFKYPERPIIFLSACYLFVSVGYLVRLVAGHEKVACSGGAPGAGGAGGAGGAAAGA
GAAGAGAGGPGGRGEYEELGAVEQHVRYETTGPALCTVVFLLVYFFGMASSIWWVILSLT
WFLAAGMKWGNEAIAGYSQYFHLAAWLVPSVKSIAVLALSSVDGDPVAGICYVGNQSLDN
LRGFVLAPLVIYLFIGTMFLLAGFVSLFRIRSVIKQQDGPTKTHKLEKLMIRLGLFTVLY
TVPAAVVVACLFYEQHNRPRWEATHNCPCLRDLQPDQARRPDYAVFMLKYFMCLVVGITS
GVWVWSGKTLESWRSLCTRCCWASKGAAVGGGAGATAAGGGGGPGGGGGGGPGGGGGPGG
GGGSLYSDVSTGLTWRSGTASSVSYPKQMPLSQV
Function
Receptor for Wnt proteins. Component of the Wnt-Fzd-LRP5-LRP6 complex that triggers beta-catenin signaling through inducing aggregation of receptor-ligand complexes into ribosome-sized signalosomes. The beta-catenin canonical signaling pathway leads to the activation of disheveled proteins, inhibition of GSK-3 kinase, nuclear accumulation of beta-catenin and activation of Wnt target genes. A second signaling pathway involving PKC and calcium fluxes has been seen for some family members, but it is not yet clear if it represents a distinct pathway or if it can be integrated in the canonical pathway, as PKC seems to be required for Wnt-mediated inactivation of GSK-3 kinase. Both pathways seem to involve interactions with G-proteins. May be involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Coreceptor along with RYK of Wnt proteins, such as WNT1.
Tissue Specificity Most abundant in fetal kidney, followed by brain and lung. In adult tissues, expressed in kidney, heart, pancreas and skeletal muscle.
KEGG Pathway
mTOR sig.ling pathway (hsa04150 )
Wnt sig.ling pathway (hsa04310 )
Hippo sig.ling pathway (hsa04390 )
Sig.ling pathways regulating pluripotency of stem cells (hsa04550 )
Melanogenesis (hsa04916 )
Cushing syndrome (hsa04934 )
Alzheimer disease (hsa05010 )
Pathways of neurodegeneration - multiple diseases (hsa05022 )
Human papillomavirus infection (hsa05165 )
Pathways in cancer (hsa05200 )
Proteoglycans in cancer (hsa05205 )
Basal cell carcinoma (hsa05217 )
Breast cancer (hsa05224 )
Hepatocellular carcinoma (hsa05225 )
Gastric cancer (hsa05226 )
Reactome Pathway
Asymmetric localization of PCP proteins (R-HSA-4608870 )
Regulation of FZD by ubiquitination (R-HSA-4641263 )
Signaling by RNF43 mutants (R-HSA-5340588 )
Class B/2 (Secretin family receptors) (R-HSA-373080 )

Molecular Interaction Atlas (MIA) of This DOT

22 Disease(s) Related to This DOT
Disease Name Disease ID Evidence Level Mode of Inheritance REF
Advanced cancer DISAT1Z9 Strong Genetic Variation [1]
Chronic bronchitis DISS8O8V Strong Biomarker [2]
Clear cell renal carcinoma DISBXRFJ Strong Altered Expression [3]
Colorectal carcinoma DIS5PYL0 Strong Biomarker [4]
Gastric cancer DISXGOUK Strong Biomarker [5]
Interstitial cystitis DIS7CAJA Strong Biomarker [6]
Lung cancer DISCM4YA Strong Altered Expression [7]
Lung carcinoma DISTR26C Strong Altered Expression [7]
Metastatic malignant neoplasm DIS86UK6 Strong Biomarker [4]
Neoplasm DISZKGEW Strong Biomarker [4]
Non-small-cell lung cancer DIS5Y6R9 Strong Altered Expression [8]
Psoriasis DIS59VMN Strong Biomarker [9]
Renal cell carcinoma DISQZ2X8 Strong Altered Expression [3]
Stomach cancer DISKIJSX Strong Biomarker [5]
Triple negative breast cancer DISAMG6N Strong Altered Expression [10]
Prostate cancer DISF190Y moderate Altered Expression [11]
Prostate carcinoma DISMJPLE moderate Altered Expression [11]
Bone osteosarcoma DIST1004 Limited Altered Expression [12]
Osteosarcoma DISLQ7E2 Limited Altered Expression [12]
Thyroid cancer DIS3VLDH Limited Altered Expression [13]
Thyroid gland carcinoma DISMNGZ0 Limited Altered Expression [13]
Thyroid tumor DISLVKMD Limited Altered Expression [13]
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⏷ Show the Full List of 22 Disease(s)
Molecular Interaction Atlas (MIA) Jump to Detail Molecular Interaction Atlas of This DOT
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 Frizzled-8 (FZD8). [14]
Camptothecin DM6CHNJ Phase 3 Camptothecin decreases the methylation of Frizzled-8 (FZD8). [22]
Benzo(a)pyrene DMN7J43 Phase 1 Benzo(a)pyrene increases the methylation of Frizzled-8 (FZD8). [23]
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10 Drug(s) Affected the Gene/Protein Processing of This DOT
Drug Name Drug ID Highest Status Interaction REF
Tretinoin DM49DUI Approved Tretinoin affects the expression of Frizzled-8 (FZD8). [15]
Acetaminophen DMUIE76 Approved Acetaminophen increases the expression of Frizzled-8 (FZD8). [16]
Cupric Sulfate DMP0NFQ Approved Cupric Sulfate increases the expression of Frizzled-8 (FZD8). [17]
Estradiol DMUNTE3 Approved Estradiol decreases the expression of Frizzled-8 (FZD8). [18]
Carbamazepine DMZOLBI Approved Carbamazepine affects the expression of Frizzled-8 (FZD8). [19]
Thalidomide DM70BU5 Approved Thalidomide decreases the expression of Frizzled-8 (FZD8). [20]
SNDX-275 DMH7W9X Phase 3 SNDX-275 decreases the expression of Frizzled-8 (FZD8). [21]
Trichostatin A DM9C8NX Investigative Trichostatin A decreases the expression of Frizzled-8 (FZD8). [21]
Deguelin DMXT7WG Investigative Deguelin increases the expression of Frizzled-8 (FZD8). [24]
KOJIC ACID DMP84CS Investigative KOJIC ACID increases the expression of Frizzled-8 (FZD8). [25]
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⏷ Show the Full List of 10 Drug(s)

References

1 Pathogenic Epigenetic Consequences of Genetic Alterations in IDH-Wild-Type Diffuse Astrocytic Gliomas.Cancer Res. 2019 Oct 1;79(19):4814-4827. doi: 10.1158/0008-5472.CAN-19-1272. Epub 2019 Aug 20.
2 A pro-inflammatory role for the Frizzled-8 receptor in chronic bronchitis.Thorax. 2016 Apr;71(4):312-22. doi: 10.1136/thoraxjnl-2015-206958. Epub 2016 Jan 21.
3 Frizzled 8 promotes the cell proliferation and metastasis of renal cell carcinoma.Oncotarget. 2017 Sep 8;8(45):78989-79002. doi: 10.18632/oncotarget.20742. eCollection 2017 Oct 3.
4 MicroRNA-375 suppresses human colorectal cancer metastasis by targeting Frizzled 8.Oncotarget. 2016 Jun 28;7(26):40644-40656. doi: 10.18632/oncotarget.9811.
5 Expression profiles of 10 members of Frizzled gene family in human gastric cancer.Int J Oncol. 2001 Oct;19(4):767-71. doi: 10.3892/ijo.19.4.767.
6 Quantitative proteomics identifies a beta-catenin network as an element of the signaling response to Frizzled-8 protein-related antiproliferative factor.Mol Cell Proteomics. 2011 Jun;10(6):M110.007492. doi: 10.1074/mcp.M110.007492. Epub 2011 Mar 21.
7 Frizzled-8 as a putative therapeutic target in human lung cancer.Biochem Biophys Res Commun. 2012 Jan 6;417(1):62-6. doi: 10.1016/j.bbrc.2011.11.055. Epub 2011 Nov 25.
8 miRNA-99b-5p targets FZD8 to inhibit non-small cell lung cancer proliferation, migration and invasion.Onco Targets Ther. 2019 Apr 8;12:2615-2621. doi: 10.2147/OTT.S199196. eCollection 2019.
9 MiR-99a inhibits keratinocyte proliferation by targeting Frizzled-5 (FZD5) / FZD8 through -catenin signaling in psoriasis.Pharmazie. 2017 Aug 1;72(8):461-467. doi: 10.1691/ph.2017.7018.
10 Tumor-initiating cells and FZD8 play a major role in drug resistance in triple-negative breast cancer.Mol Cancer Ther. 2013 Apr;12(4):491-8. doi: 10.1158/1535-7163.MCT-12-1090. Epub 2013 Feb 27.
11 Frizzled-8 integrates Wnt-11 and transforming growth factor- signaling in prostate cancer.Nat Commun. 2018 May 1;9(1):1747. doi: 10.1038/s41467-018-04042-w.
12 MicroRNA-520b Suppresses Proliferation, Migration, and Invasion of Spinal Osteosarcoma Cells via Downregulation of Frizzled-8.Oncol Res. 2017 Sep 21;25(8):1297-1304. doi: 10.3727/096504017X14873430389189. Epub 2017 Feb 28.
13 Emerging roles of circRNA_NEK6 targeting miR-370-3p in the proliferation and invasion of thyroid cancer via Wnt signaling pathway.Cancer Biol Ther. 2018;19(12):1139-1152. doi: 10.1080/15384047.2018.1480888. Epub 2018 Sep 12.
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 Molecular characterization of a toxicological tipping point during human stem cell differentiation. Reprod Toxicol. 2020 Jan;91:1-13. doi: 10.1016/j.reprotox.2019.10.001. Epub 2019 Oct 7.
16 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.
17 Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
18 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.
19 Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
20 A high-throughput screen for teratogens using human pluripotent stem cells. Toxicol Sci. 2014 Jan;137(1):76-90. doi: 10.1093/toxsci/kft239. Epub 2013 Oct 23.
21 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.
22 Reduced camptothecin sensitivity of estrogen receptor-positive human breast cancer cells following exposure to di(2-ethylhexyl)phthalate (DEHP) is associated with DNA methylation changes. Environ Toxicol. 2019 Apr;34(4):401-414.
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 Deguelin inhibits growth of breast cancer cells by modulating the expression of key members of the Wnt signaling pathway. Cancer Prev Res (Phila). 2009 Nov;2(11):942-50. doi: 10.1158/1940-6207.CAPR-08-0232. Epub 2009 Oct 27.
25 Toxicogenomics of kojic acid on gene expression profiling of a375 human malignant melanoma cells. Biol Pharm Bull. 2006 Apr;29(4):655-69.