Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTIWDN78)

DOT Name	Frizzled-3 (FZD3)
Synonyms	Fz-3; hFz3
Gene Name	FZD3
Related Disease	Acute myelogenous leukaemia ( ) Alzheimer disease ( ) Autism ( ) Breast cancer ( ) Breast carcinoma ( ) Colorectal carcinoma ( ) Congenital hydrocephalus ( ) Familial adenomatous polyposis ( ) Hepatocellular carcinoma ( ) Hydrocephalus ( ) Melanoma ( ) Myotonic dystrophy type 1 ( ) Neoplasm ( ) Neural tube defect ( ) Polycystic ovarian syndrome ( ) Sarcoma ( ) Small lymphocytic lymphoma ( ) Type-1/2 diabetes ( ) Ulcerative colitis ( ) Peripheral sensory neuropathies ( ) Gastric cancer ( ) Hirschsprung disease ( ) Stomach cancer ( )
UniProt ID	FZD3_HUMAN
3D Structure	Download 2D Sequence (FASTA) Download 3D Structure (PDB) Download
Pfam ID	PF01534 ; PF01392
Sequence	MAMTWIVFSLWPLTVFMGHIGGHSLFSCEPITLRMCQDLPYNTTFMPNLLNHYDQQTAAL AMEPFHPMVNLDCSRDFRPFLCALYAPICMEYGRVTLPCRRLCQRAYSECSKLMEMFGVP WPEDMECSRFPDCDEPYPRLVDLNLAGEPTEGAPVAVQRDYGFWCPRELKIDPDLGYSFL HVRDCSPPCPNMYFRREELSFARYFIGLISIICLSATLFTFLTFLIDVTRFRYPERPIIF YAVCYMMVSLIFFIGFLLEDRVACNASIPAQYKASTVTQGSHNKACTMLFMILYFFTMAG SVWWVILTITWFLAAVPKWGSEAIEKKALLFHASAWGIPGTLTIILLAMNKIEGDNISGV CFVGLYDVDALRYFVLAPLCLYVVVGVSLLLAGIISLNRVRIEIPLEKENQDKLVKFMIR IGVFSILYLVPLLVVIGCYFYEQAYRGIWETTWIQERCREYHIPCPYQVTQMSRPDLILF LMKYLMALIVGIPSVFWVGSKKTCFEWASFFHGRRKKEIVNESRQVLQEPDFAQSLLRDP NTPIIRKSRGTSTQGTSTHASSTQLAMVDDQRSKAGSIHSKVSSYHGSLHRSRDGRYTPC SYRGMEERLPHGSMSRLTDHSRHSSSHRLNEQSRHSSIRDLSNNPMTHITHGTSMNRVIE EDGTSA
Function	Receptor for Wnt proteins. Most of frizzled receptors are coupled to the beta-catenin canonical signaling pathway, which 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. Activation by Wnt5A stimulates PKC activity via a G-protein-dependent mechanism. Involved in transduction and intercellular transmission of polarity information during tissue morphogenesis and/or in differentiated tissues. Plays a role in controlling early axon growth and guidance processes necessary for the formation of a subset of central and peripheral major fiber tracts. Required for the development of major fiber tracts in the central nervous system, including: the anterior commissure, the corpus callosum, the thalamocortical, corticothalamic and nigrostriatal tracts, the corticospinal tract, the fasciculus retroflexus, the mammillothalamic tract, the medial lemniscus, and ascending fiber tracts from the spinal cord to the brain. In the peripheral nervous system, controls axon growth in distinct populations of cranial and spinal motor neurons, including the facial branchimotor nerve, the hypoglossal nerve, the phrenic nerve, and motor nerves innervating dorsal limbs. Involved in the migration of cranial neural crest cells. May also be implicated in the transmission of sensory information from the trunk and limbs to the brain. Controls commissural sensory axons guidance after midline crossing along the anterior-posterior axis in the developing spinal cord in a Wnt-dependent signaling pathway. Together with FZD6, is involved in the neural tube closure and plays a role in the regulation of the establishment of planar cell polarity (PCP), particularly in the orientation of asymmetric bundles of stereocilia on the apical faces of a subset of auditory and vestibular sensory cells located in the inner ear. Promotes neurogenesis by maintaining sympathetic neuroblasts within the cell cycle in a beta-catenin-dependent manner.
Tissue Specificity	Widely expressed. Relatively high expression in the CNS, including regions of the limbic system, in kidney, pancreas, skeletal muscle, uterus and testis.
KEGG Pathway	mTOR sig.ling pathway (hsa04150 ) Wnt sig.ling pathway (hsa04310 ) Axon guidance (hsa04360 ) 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 ) MicroR.s in cancer (hsa05206 ) Basal cell carcinoma (hsa05217 ) Breast cancer (hsa05224 ) Hepatocellular carcinoma (hsa05225 ) Gastric cancer (hsa05226 )
Reactome Pathway	Ca2+ pathway (R-HSA-4086398 ) PCP/CE pathway (R-HSA-4086400 ) Asymmetric localization of PCP proteins (R-HSA-4608870 ) Class B/2 (Secretin family receptors) (R-HSA-373080 )

Molecular Interaction Atlas (MIA) of This DOT

23 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance
Acute myelogenous leukaemia	DISCSPTN	Strong	Biomarker	[1]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[2]
Autism	DISV4V1Z	Strong	Biomarker	[3]
Breast cancer	DIS7DPX1	Strong	Biomarker	[4]
Breast carcinoma	DIS2UE88	Strong	Biomarker	[4]
Colorectal carcinoma	DIS5PYL0	Strong	Genetic Variation	[5]
Congenital hydrocephalus	DIS7O6UL	Strong	Posttranslational Modification	[6]
Familial adenomatous polyposis	DISW53RE	Strong	Altered Expression	[7]
Hepatocellular carcinoma	DIS0J828	Strong	Altered Expression	[8]
Hydrocephalus	DISIZUF7	Strong	Genetic Variation	[6]
Melanoma	DIS1RRCY	Strong	Altered Expression	[9]
Myotonic dystrophy type 1	DISJC0OX	Strong	Biomarker	[10]
Neoplasm	DISZKGEW	Strong	Altered Expression	[9]
Neural tube defect	DIS5J95E	Strong	Posttranslational Modification	[11]
Polycystic ovarian syndrome	DISZ2BNG	Strong	Altered Expression	[12]
Sarcoma	DISZDG3U	Strong	Altered Expression	[13]
Small lymphocytic lymphoma	DIS30POX	Strong	Altered Expression	[14]
Type-1/2 diabetes	DISIUHAP	Strong	Biomarker	[10]
Ulcerative colitis	DIS8K27O	Strong	Altered Expression	[15]
Peripheral sensory neuropathies	DISYWI6M	moderate	Genetic Variation	[16]
Gastric cancer	DISXGOUK	Limited	Biomarker	[17]
Hirschsprung disease	DISUUSM1	Limited	Biomarker	[18]
Stomach cancer	DISKIJSX	Limited	Biomarker	[17]
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⏷ Show the Full List of 23 Disease(s)

Molecular Interaction Atlas (MIA)

MIA Detail

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 decreases the methylation of Frizzled-3 (FZD3).	[19]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of Frizzled-3 (FZD3).	[23]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the methylation of Frizzled-3 (FZD3).	[31]
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16 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Frizzled-3 (FZD3).	[20]
Tretinoin	DM49DUI	Approved	Tretinoin decreases the expression of Frizzled-3 (FZD3).	[21]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Frizzled-3 (FZD3).	[22]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Frizzled-3 (FZD3).	[24]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Frizzled-3 (FZD3).	[25]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Frizzled-3 (FZD3).	[26]
Panobinostat	DM58WKG	Approved	Panobinostat decreases the expression of Frizzled-3 (FZD3).	[27]
Diclofenac	DMPIHLS	Approved	Diclofenac affects the expression of Frizzled-3 (FZD3).	[25]
Clorgyline	DMCEUJD	Approved	Clorgyline increases the expression of Frizzled-3 (FZD3).	[28]
Adenosine	DMM2NSK	Approved	Adenosine increases the expression of Frizzled-3 (FZD3).	[29]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Frizzled-3 (FZD3).	[27]
Genistein	DM0JETC	Phase 2/3	Genistein increases the expression of Frizzled-3 (FZD3).	[30]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A decreases the expression of Frizzled-3 (FZD3).	[32]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Frizzled-3 (FZD3).	[33]
Lithium chloride	DMHYLQ2	Investigative	Lithium chloride increases the expression of Frizzled-3 (FZD3).	[34]
Cordycepin	DM72Y01	Investigative	Cordycepin increases the expression of Frizzled-3 (FZD3).	[29]
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⏷ Show the Full List of 16 Drug(s)

References

1	Investigating the microRNA-mRNA regulatory network in acute myeloid leukemia.Oncol Lett. 2017 Oct;14(4):3981-3988. doi: 10.3892/ol.2017.6686. Epub 2017 Jul 28.
2	Silencing of Long Noncoding RNA SOX21-AS1 Relieves Neuronal Oxidative Stress Injury in Mice with Alzheimer's Disease by Upregulating FZD3/5 via the Wnt Signaling Pathway.Mol Neurobiol. 2019 May;56(5):3522-3537. doi: 10.1007/s12035-018-1299-y. Epub 2018 Aug 24.
3	Over-expressed LOC101927196 suppressed oxidative stress levels and neuron cell proliferation in a rat model of autism through disrupting the Wnt signaling pathway by targeting FZD3.Cell Signal. 2019 Oct;62:109328. doi: 10.1016/j.cellsig.2019.05.013. Epub 2019 May 27.
4	A tRNA fragment, 5'-tiRNA(Val), suppresses the Wnt/-catenin signaling pathway by targeting FZD3 in breast cancer.Cancer Lett. 2019 Aug 10;457:60-73. doi: 10.1016/j.canlet.2019.05.007. Epub 2019 May 9.
5	Germline Genetic Variants in the Wnt/-Catenin Pathway as Predictors of Colorectal Cancer Risk.Cancer Epidemiol Biomarkers Prev. 2016 Mar;25(3):540-6. doi: 10.1158/1055-9965.EPI-15-0834. Epub 2016 Jan 25.
6	Impaired methylation modifications of FZD3 alter chromatin accessibility and are involved in congenital hydrocephalus pathogenesis.Brain Res. 2014 Jun 20;1569:48-56. doi: 10.1016/j.brainres.2014.04.010. Epub 2014 May 2.
7	Wnt signalling in adenomas of familial adenomatous polyposis patients.Br J Cancer. 2010 Sep 7;103(6):910-7. doi: 10.1038/sj.bjc.6605790. Epub 2010 Jul 13.
8	Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma.Br J Cancer. 2008 Jul 8;99(1):143-50. doi: 10.1038/sj.bjc.6604422. Epub 2008 Jun 24.
9	Down-regulation of FZD3 receptor suppresses growth and metastasis of human melanoma independently of canonical WNT signaling.Proc Natl Acad Sci U S A. 2019 Mar 5;116(10):4548-4557. doi: 10.1073/pnas.1813802116. Epub 2019 Feb 21.
10	The synthetic pyrethroid deltamethrin impairs zebrafish (Danio rerio) swim bladder development.Sci Total Environ. 2020 Jan 20;701:134870. doi: 10.1016/j.scitotenv.2019.134870. Epub 2019 Oct 31.
11	DNA methylation aberrations rather than polymorphisms of FZD3 gene increase the risk of spina bifida in a high-risk region for neural tube defects.Birth Defects Res A Clin Mol Teratol. 2015 Jan;103(1):37-44. doi: 10.1002/bdra.23285. Epub 2014 Aug 18.
12	Deregulation of WNT2/FZD3/-catenin pathway compromises the estrogen synthesis in cumulus cells from patients with polycystic ovary syndrome.Biochem Biophys Res Commun. 2017 Nov 4;493(1):847-854. doi: 10.1016/j.bbrc.2017.07.057. Epub 2017 Jul 11.
13	Wnt-3a and Dickkopf-1 stimulate neurite outgrowth in Ewing tumor cells via a Frizzled3- and c-Jun N-terminal kinase-dependent mechanism.Mol Cell Biol. 2008 Apr;28(7):2368-79. doi: 10.1128/MCB.01780-07. Epub 2008 Jan 22.
14	Activation of the Wnt signaling pathway in chronic lymphocytic leukemia.Proc Natl Acad Sci U S A. 2004 Mar 2;101(9):3118-23. doi: 10.1073/pnas.0308648100. Epub 2004 Feb 18.
15	Wnt pathway-related gene expression in inflammatory bowel disease.Dig Dis Sci. 2008 Apr;53(4):1013-9. doi: 10.1007/s10620-007-9973-3. Epub 2007 Oct 16.
16	A genome-wide association study identifies novel loci for paclitaxel-induced sensory peripheral neuropathy in CALGB 40101.Clin Cancer Res. 2012 Sep 15;18(18):5099-109. doi: 10.1158/1078-0432.CCR-12-1590. Epub 2012 Jul 27.
17	WNT/PCP signaling pathway and human cancer (review).Oncol Rep. 2005 Dec;14(6):1583-8.
18	Preliminary identification of key miRNAs, signaling pathways, and genes associated with Hirschsprung's disease by analysis of tissue microRNA expression profiles.World J Pediatr. 2017 Oct;13(5):489-495. doi: 10.1007/s12519-017-0064-z. Epub 2017 Sep 30.
19	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.
20	Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
21	Development of a neural teratogenicity test based on human embryonic stem cells: response to retinoic acid exposure. Toxicol Sci. 2011 Dec;124(2):370-7.
22	Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
23	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.
24	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.
25	Drug-induced endoplasmic reticulum and oxidative stress responses independently sensitize toward TNF-mediated hepatotoxicity. Toxicol Sci. 2014 Jul;140(1):144-59. doi: 10.1093/toxsci/kfu072. Epub 2014 Apr 20.
26	Global molecular effects of tocilizumab therapy in rheumatoid arthritis synovium. Arthritis Rheumatol. 2014 Jan;66(1):15-23.
27	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.
28	Anti-oncogenic and pro-differentiation effects of clorgyline, a monoamine oxidase A inhibitor, on high grade prostate cancer cells. BMC Med Genomics. 2009 Aug 20;2:55. doi: 10.1186/1755-8794-2-55.
29	Adenosine and Cordycepin Accelerate Tissue Remodeling Process through Adenosine Receptor Mediated Wnt/-Catenin Pathway Stimulation by Regulating GSK3b Activity. Int J Mol Sci. 2021 May 25;22(11):5571. doi: 10.3390/ijms22115571.
30	The molecular basis of genistein-induced mitotic arrest and exit of self-renewal in embryonal carcinoma and primary cancer cell lines. BMC Med Genomics. 2008 Oct 10;1:49.
31	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.
32	Epigenetic changes and disturbed neural development in a human embryonic stem cell-based model relating to the fetal valproate syndrome. Hum Mol Genet. 2012 Sep 15;21(18):4104-14. doi: 10.1093/hmg/dds239. Epub 2012 Jun 20.
33	Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.
34	Lithium chloride regulates the proliferation of stem-like cells in retinoblastoma cell lines: a potential role for the canonical Wnt signaling pathway. Mol Vis. 2010 Jan 13;16:36-45.