FZD<sub>3</sub> | Class Frizzled GPCRs | IUPHAR/BPS Guide to PHARMACOLOGY

FZD3

Target id: 231

Nomenclature: FZD3

Family: Class Frizzled GPCRs

Annotation status:  image of a green circle Annotated and expert reviewed. Please contact us if you can help with updates.  » Email us

   GtoImmuPdb view: OFF :     Currently no data for FZD3 in GtoImmuPdb

Gene and Protein Information
Frizzled family G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 666 8p21 FZD3 frizzled class receptor 3 10,16
Mouse 7 666 14 D1; 14 34.09 cM Fzd3 frizzled class receptor 3 20
Rat 7 666 15 Fzd3 frizzled class receptor 3
Previous and Unofficial Names
Fz3 | frizzled 3 | frizzled family receptor 3 | frizzled homolog 3
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Comments: The is some evidence for Wnt-5a and Wnt-3 binding to the receptor
Agonist Comments
FZDs are receptors for WNT proteins. Until now FZD3 has been proven to bind to WNT 2, 3A and 5A. For more detail information see [2].
Primary Transduction Mechanisms
Transducer Effector/Response
Gs family
G protein (identity unknown)
Comments:  The role of heterotrimeric G proteins in signal transduction has not been addressed for FZD3 in detail yet.

WNT-3A enhances beta-catenin dependent transcription [23] and WNT-5A induces Akt phosphorylation via the phosphatidylinositol-3 kinase pathway [9]. FZD3 was found to activate the Gαs/cAMP/PKA pathway, resulting in the phosphorylation of Thr34 of DARPP-32 (dopamine- and cAMP-regulated neuronal phosphoprotein-32) [4].
References:  9,23
Tissue Distribution
Significantly increased FZD3 expression in ulcerative colitis tissue
Species:  Human
Technique:  Microarray analysis
References:  27
FZD3 is overexpressed in human hepatocellular carcinoma (HCC) cell line
Species:  Human
Technique:  RT-PCR
References:  1
High FZD3 expression in chronic lymphocytic leukemia B cells
Species:  Human
Technique:  RT-PCR
References:  11
High FZD3 expression in lymphoma cell lines (Namalwa, Daudi, ST486)
Species:  Human
Technique:  RT-PCR
References:  15
Adult: FZD3 is expressed in olfactory sensory neurons.
Species:  Mouse
Technique:  Microarray analysis, in situ hybridization
References:  17
Developing: FZD3 is expressed in pancreatic epithelium
Species:  Mouse
Technique:  RT-PCR
References:  14
Adult: brain, eye, lung and testis.
Developing: central nervous system.
Species:  Mouse
Technique:  RNA protection assay (adult), in situ hybridisation (during development)
References:  20
Adult: brain (cerebral cortex, hypothalamus > hippocampus) kidneys, uterus and testis
Species:  Rat
Technique:  Northern blot
References:  24
Expression Datasets

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Log average relative transcript abundance in mouse tissues measured by qPCR from Regard, J.B., Sato, I.T., and Coughlin, S.R. (2008). Anatomical profiling of G protein-coupled receptor expression. Cell, 135(3): 561-71. [PMID:18984166] [Raw data: website]

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Functional Assays
Measurement of Vangl2 and FZD3 interaction via immunoprecipitation in HEK293 cells. Detection of Vangl2 and FZD3 colocalization in P1 rat cochlea.
Species:  Rat
Tissue:  P1 rat cochlea, HEK293 cells
Response measured:  Polarity of receptor localization, Vangl2 and FZD3 interaction
References:  13
Measurement of WNT-3A induced neurite outgrowth in TC-32 cells via FZD3 and a JNK dependent mechanism.
Species:  Human
Tissue:  TC-32 cells (Ewing sarcoma family of tumors)
Response measured:  Neurite outgrowth, JNK activation
References:  3
Measurement of WNT-5A induced cell polarity and cell movement in WM239A melanoma cell line. Detection of FZD3 colocalization with M-CAM (melanoma cell adhesion molecule), F-actin and myosin IIB.
Species:  Human
Tissue:  WM239A melanoma cell line
Response measured:  Polarity of receptor localization, RhoB activation
References:  23
Measurement of WNT-5A stimulated PI3K/Akt activation in primary cultured dermal fibroblasts.
Species:  Human
Tissue:  Primary cultured dermal fibroblasts
Response measured:  Activation of PI3K, PKB/Akt
References:  9
Measurement of FZD3 phosphorylation in HEK293T cells transfected with FZD3 and myc-Dvl and incubated with 32PO4.
Species:  Human
Tissue:  HEK293T
Response measured:  Phosphorylation of FZD3
References:  25
Measurement of TCF/LEF transcriptional activity (using the TOPflash reporter) in HEK293 cells transfected with human FZD3, LRP6 and WNT-3
Species:  Human
Tissue:  HEK293 cells
Response measured:  Activation of TCF/LEF promotor activity (TOPflash)
References:  11
Physiological Functions
FZD3 is crucial for the guidance of commissural axons along the anterior-posterior axis of the spinal cord.
Species:  Mouse
Tissue:  Brain, developing mouse
References:  12
FZD3 is crucial for neural tube closure and the planar orientation of a subset of auditory and vestibular sensory cells in developing mice.
Species:  Mouse
Tissue:  Brain, developing mouse
References:  19,21
Physiological Consequences of Altering Gene Expression
The FZD3 knock-out shows severe defects in several major axon tracts within the forebrain, including complete loss of the thalamocortical, corticothalamic, and nigrostriatal tracts and of the anterior commissure.
Species:  Mouse
Tissue: 
Technique:  Transgenesis
References:  21
The following tracts are absent or greatly reduced in FZD3 knock-out mice: Anterior commissure, cerebral peduncle (corticospinal tract), corpus callosum, fornix, internal capsule (thalamocortical and corticothalamic tracts), stria medullaris, stria terminalis, and hippocampal commissure, however the PNS appears nearly normal.
Species:  Mouse
Tissue: 
Technique:  Transgenesis
References:  24
Fzd3 and Fzd6 deficiency results in a severe midbrain morphogenesis defect
Species:  Mouse
Tissue:  Midbrain
Technique:  Gene knockouts
References:  18
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0001951 abnormal breathing pattern PMID: 12351730 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0000031 abnormal cochlea morphology PMID: 16495441 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0004399 abnormal cochlear outer hair cell morphology PMID: 16495441 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0004249 abnormal crista ampullaris morphology PMID: 16495441 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0000556 abnormal hindlimb morphology PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0001175 abnormal lung morphology PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0000778 abnormal nervous system tract PMID: 12351730 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0004492 abnormal orientation of inner hair cell stereociliary bundles PMID: 16495441 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0000955 abnormal spinal cord morphology PMID: 14671310 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0004077 abnormal striatum morphology PMID: 12351730 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0003149 abnormal tectorial membrane morphology PMID: 16495441 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0000787 abnormal telencephalon morphology PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0001529 abnormal vocalization PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0008227 absent anterior commissure PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0008129 absent brain internal capsule PMID: 14671310 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0003051 curly tail PMID: 12351730 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0003051 curly tail PMID: 16495441 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0001575 cyanosis PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0000781 decreased corpus callosum size PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0008535 enlarged lateral ventricles PMID: 12351730 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0001302 eyelids open at birth PMID: 16495441 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0000928 incomplete cephalic closure PMID: 12351730 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0002058 neonatal lethality PMID: 12351730 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0002058 neonatal lethality PMID: 16495441 
Fzd3+|Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3+,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0002687 oligozoospermia PMID: 16495441 
Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0000929 open neural tube PMID: 16495441 
Fzd3+|Fzd3tm1Nat|Fzd6tm1Nat Fzd3tm1Nat/Fzd3+,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108474  MGI:108476  MP:0001922 reduced male fertility PMID: 16495441 
Fzd3tm1Nat Fzd3tm1Nat/Fzd3tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6
MGI:108476  MP:0006254 thin cerebral cortex PMID: 12351730 
Clinically-Relevant Mutations and Pathophysiology
Disease:  Chronic lymphocytic leukemia
Synonyms: B-cell chronic lymphocytic leukemia [Orphanet: ORPHA67038]
Chronic lymphatic leukemia
Chronic lymphoid leukemia
Disease Ontology: DOID:1040
OMIM: 151400
Orphanet: ORPHA67038
References:  8,11
Disease:  Schizophrenia
Disease Ontology: DOID:5419
OMIM: 181500
Orphanet: ORPHA3140
References:  7,22,26,28
Biologically Significant Variants
Type:  Single nucleotide polymorphism
Species:  Human
Description:  SNPs (rs2241802, rs2323019) in FZD3 are probably involved in schizophrenia, however there is controversial evidence about the association of certain FZD3 SNPs and schizophrenia.
SNP accession: 
References:  5-6

References

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1. Bengochea A, de Souza MM, Lefrançois L, Le Roux E, Galy O, Chemin I, Kim M, Wands JR, Trepo C, Hainaut P, Scoazec JY, Vitvitski L, Merle P. (2008) Common dysregulation of Wnt/Frizzled receptor elements in human hepatocellular carcinoma. Br J Cancer, 99: 143-150. [PMID:18577996]

2. Dijksterhuis JP, Petersen J, Schulte G. (2013) WNT/Frizzled signaling: receptor-ligand selectivity with focus on FZD-G protein signaling and its physiological relevance. Br J Pharmacol,. [PMID:24032637]

3. Endo Y, Beauchamp E, Woods D, Taylor WG, Toretsky JA, Uren A, Rubin JS. (2008) 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, 28: 2368-2379. [PMID:18212053]

4. Hansen C, Howlin J, Tengholm A, Dyachok O, Vogel WF, Nairn AC, Greengard P, Andersson T. (2009) Wnt-5a-induced phosphorylation of DARPP-32 inhibits breast cancer cell migration in a CREB-dependent manner. J. Biol. Chem., 284 (40): 27533-43. [PMID:19651774]

5. Ide M, Muratake T, Yamada K, Iwayama-Shigeno Y, Iwamoto K, Takao H, Toyota T, Kaneko N, Minabe Y, Nakamura K, Kato T, Mori N, Asada T, Someya T, Yoshikawa T. (2004) Genetic and expression analyses of FZD3 in schizophrenia. Biol Psychiatry, 56: 462-465. [PMID:15364045]

6. Kang G, Yue W, Zhang J, Huebner M, Zhang H, Ruan Y, Lu T, Ling Y, Zuo Y, Zhang D. (2008) Two-stage designs to identify the effects of SNP combinations on complex diseases. J Hum Genet, 53: 739-746. [PMID:18584117]

7. Katsu T, Ujike H, Nakano T, Tanaka Y, Nomura A, Nakata K, Takaki M, Sakai A, Uchida N, Imamura T et al.. (2003) The human frizzled-3 (FZD3) gene on chromosome 8p21, a receptor gene for Wnt ligands, is associated with the susceptibility to schizophrenia. Neurosci. Lett., 353 (1): 53-6. [PMID:14642436]

8. Kaucká M, Plevová K, Pavlová S, Janovská P, Mishra A, Verner J, Procházková J, Krejcí P, Kotasková J, Ovesná P et al.. (2013) The planar cell polarity pathway drives pathogenesis of chronic lymphocytic leukemia by the regulation of B-lymphocyte migration. Cancer Res., 73 (5): 1491-501. [PMID:23338609]

9. Kawasaki A, Torii K, Yamashita Y, Nishizawa K, Kanekura K, Katada M, Ito M, Nishimoto I, Terashita K, Aiso S, Matsuoka M. (2007) Wnt5a promotes adhesion of human dermal fibroblasts by triggering a phosphatidylinositol-3 kinase/Akt signal. Cell Signal, 19: 2498-2506. [PMID:17804197]

10. Kirikoshi H, Koike J, Sagara N, Saitoh T, Tokuhara M, Tanaka K, Sekihara H, Hirai M, Katoh M. (2000) Molecular cloning and genomic structure of human frizzled-3 at chromosome 8p21. Biochem Biophys Res Commun, 271: 8-14. [PMID:10777673]

11. Lu D, Zhao Y, Tawatao R, Cottam HB, Sen M, Leoni LM, Kipps TJ, Corr M, Carson DA. (2004) Activation of the Wnt signaling pathway in chronic lymphocytic leukemia. Proc Natl Acad Sci U S A, 101: 3118-3123. [PMID:14973184]

12. Lyuksyutova AI, Lu CC, Milanesio N, King LA, Guo N, Wang Y, Nathans J, Tessier-Lavigne M, Zou Y. (2003) Anterior-posterior guidance of commissural axons by Wnt-frizzled signaling. Science, 302: 1984-1988. [PMID:14671310]

13. Montcouquiol M, Sans N, Huss D, Kach J, Dickman JD, Forge A, Rachel RA, Copeland NG, Jenkins NA, Bogani D, Murdoch J, Warchol ME, Wenthold RJ, Kelley MW. (2006) Asymmetric localization of Vangl2 and Fz3 indicate novel mechanisms for planar cell polarity in mammals. J Neurosci, 26: 5265-5275. [PMID:16687519]

14. Papadopoulou S, Edlund H. (2005) Attenuated Wnt signaling perturbs pancreatic growth but not pancreatic function. Diabetes, 54: 2844-2851. [PMID:16186384]

15. Povelones M, Nusse R. (2005) The role of the cysteine-rich domain of Frizzled in Wingless-Armadillo signaling. EMBO J, 24: 3493-3503. [PMID:16163385]

16. Sala CF, Formenti E, Terstappen GC, Caricasole A. (2000) Identification, gene structure, and expression of human frizzled-3 (FZD3). Biochem Biophys Res Commun, 273: 27-34. [PMID:10873558]

17. Sammeta N, Yu TT, Bose SC, McClintock TS. (2007) Mouse olfactory sensory neurons express 10,000 genes. J Comp Neurol, 502: 1138-1156. [PMID:17444493]

18. Stuebner S, Faus-Kessler T, Fischer T, Wurst W, Prakash N. (2010) Fzd3 and Fzd6 deficiency results in a severe midbrain morphogenesis defect. Dev. Dyn., 239 (1): 246-60. [PMID:19842188]

19. Wang Y, Guo N, Nathans J. (2006) The role of Frizzled3 and Frizzled6 in neural tube closure and in the planar polarity of inner-ear sensory hair cells. J Neurosci, 26: 2147-2156. [PMID:16495441]

20. Wang Y, Macke JP, Abella BS, Andreasson K, Worley P, Gilbert DJ, Copeland NG, Jenkins NA, Nathans J. (1996) A large family of putative transmembrane receptors homologous to the product of the Drosophila tissue polarity gene frizzled. J Biol Chem, 271: 4468-4476. [PMID:8626800]

21. Wang Y, Thekdi N, Smallwood PM, Macke JP, Nathans J. (2002) Frizzled-3 is required for the development of major fiber tracts in the rostral CNS. J Neurosci, 22: 8563-8573. [PMID:12351730]

22. Wei J, Hemmings GP. (2004) Lack of a genetic association between the frizzled-3 gene and schizophrenia in a British population. Neurosci. Lett., 366 (3): 336-8. [PMID:15288446]

23. Witze ES, Litman ES, Argast GM, Moon RT, Ahn NG. (2008) Wnt5a control of cell polarity and directional movement by polarized redistribution of adhesion receptors. Science, 320: 365-369. [PMID:18420933]

24. Yamada M, Iwabuchi T, Takahashi K, Kurahashi C, Ohata H, Honda K, Higuchi T, Yamada M. (2005) Identification and expression of frizzled-3 protein in rat frontal cortex after antidepressant and electroconvulsive treatment. J Pharmacol Sci, 99: 239-246. [PMID:16258230]

25. Yanfeng WA, Tan C, Fagan RJ, Klein PS. (2006) Phosphorylation of frizzled-3. J Biol Chem, 281: 11603-11609. [PMID:16513654]

26. Yang J, Si T, Ling Y, Ruan Y, Han Y, Wang X, Zhang H, Kong Q, Li X, Liu C et al.. (2003) Association study of the human FZD3 locus with schizophrenia. Biol. Psychiatry, 54 (11): 1298-301. [PMID:14643098]

27. You J, Nguyen AV, Albers CG, Lin F, Holcombe RF. (2008) Wnt pathway-related gene expression in inflammatory bowel disease. Dig Dis Sci, 53: 1013-1019. [PMID:17939044]

28. Zhang Y, Yu X, Yuan Y, Ling Y, Ruan Y, Si T, Lu T, Wu S, Gong X, Zhu Z et al.. (2004) Positive association of the human frizzled 3 (FZD3) gene haplotype with schizophrenia in Chinese Han population. Am. J. Med. Genet. B Neuropsychiatr. Genet., 129B (1): 16-9. [PMID:15274031]

Contributors

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How to cite this page

Gunnar Schulte, Jacomijn Dijksterhuis, Julian Petersen, Elisa Arthofer, Belma Hot, Katerina Strakova, Shane Wright, Jana Valnohova, Matthias Lauth.
Class Frizzled GPCRs: FZD3. Last modified on 25/06/2015. Accessed on 18/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=231.