FZD<sub>1</sub> | Class Frizzled GPCRs | IUPHAR/BPS Guide to PHARMACOLOGY

FZD1

Target id: 229

Nomenclature: FZD1

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 FZD1 in GtoImmuPdb

Gene and Protein Information
Frizzled family G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 647 7q21 FZD1 frizzled class receptor 1 9
Mouse 7 642 5 A1 Fzd1 frizzled class receptor 1 21
Rat 7 641 4q13 Fzd1 frizzled class receptor 1 2
Previous and Unofficial Names
Fz1 | Wnt receptor | Drosophila polarity gene homolog 1 | frizzled family receptor 1 | frizzled homolog 1 | Drosophila polarity gene (frizzled) homologue | Frizzled-1
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Wnt-1 {Sp: Human}
Wnt-2 {Sp: Human}
Wnt-5a {Sp: Human}
Wnt-3a {Sp: Human}
Wnt-7b {Sp: Human}
Agonist Comments
WNT-1, WNT-2, WNT-3A, WNT-5A, WNT-5B and WNT-7B bind to the FZD1 receptor [9,11,19].

Due to the lack of purified and biologically active WNTs hardly any information on the specificity and pharmacology of FZD-WNT interaction is available. Extensive and quantitative binding assays have not been performed with mammalian FZDs. The references above contain data showing the direct activation/interaction of FZD1 by individual WNTs. For additional information see [5].
Antagonist Comments
Currently no antagonists are known.
Allosteric Modulator Comments
Currently no allosteric modulators are known.
Primary Transduction Mechanisms
Transducer Effector/Response
Other - See Comments
Comments:  FZD/beta-catenin signalling (also referred to as canonical WNT signalling).
References:  7-9,19
Secondary Transduction Mechanisms
Transducer Effector/Response
Gi/Go family
Gq/G11 family
Phospholipase C stimulation
Other - See Comments
Comments:  WNT-3A induces a Gq-dependent production of IP5 and a PTX-sensitive activation of casein kinase 2, which are involved in FZD/beta-catenin signalling. In addition, FZD1 was shown to mediate Go activation (GDP/GTP exchange) in membranes from FZD1 overexpressing mammalian cells [11].
References:  7-8
Tissue Distribution
Heart, placenta, lung, kidney, pancreas, prostate, ovary >> brain, skeletal muscle, testis, small intestine, colon.
Species:  Human
Technique:  Northern blotting.
References:  16
No detection in normal colon but upregulated in colon cancer.
Species:  Human
Technique:  Immunocytochemistry.
References:  10
Developing mouse brain (E9-E12.5).
Species:  Mouse
Technique:  in situ hybridisation.
References:  6
Marker of inflammatory macrophages
Species:  Mouse
Technique:  RT-PCR.
References:  15
Mouse embryo.
Species:  Mouse
Technique:  Whole mount in situ hybridisation
References:  1
Kidney, liver, uterus, ovary, heart > brain, small intestine > calvaria, lung, mammary gland, testis.
Species:  Rat
Technique:  Northern blotting.
References:  2
Postnatal day 14 rat cochlea.
Species:  Rat
Technique:  RT-PCR.
References:  4
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
Activation of TCF/LEF transcriptional activity with a luciferase reporter (TOPflash) in HEK 293 cells transfected with the human FZD1 receptor and paracrine/autocrine co-expression of WNT-3A.
Species:  Human
Tissue:  HEK 293 cells.
Response measured:  Activation of TCF/LEF promotor activity (TOPflash).
References:  9
Measurement of WNT-3A-induced PTX-sensitive activation of casein kinase 2 activity in F9 cells stably transfected and NIH3T3/HEK 293 cells transiently transfected with the rat FZD1 receptor.
Species:  Rat
Tissue:  F9, NIH 3T3, HEK 293 cells.
Response measured:  Activation of casein kinase 2.
References:  7
Measurement of WNT-3A-induced Gq-dependent formation of IP5 via PLC, signalling through GSK3/beta-catenin and activation of TCF/Lef (TOPflash) reporter.
Species:  Rat
Tissue:  F9, HEK 293 cells.
Response measured:  Stimulation of IP5 formation.
References:  8
Measurement of Gq/o-dependent formation of primitive endoderm in a mouse teratocarcinoma cell line stimulated by Xenopus XWNT-8.
Species:  Mouse
Tissue:  F9 cells.
Response measured:  tPA activity (formation of primitive endoderm).
References:  14
FZD1 internalization
Species:  Human
Tissue:  U2OS cells
Response measured:  FZD1-GFP internalization
References:  3
FZD-mediated activation of heterotrimeric G proteins (GDP/GTP exchange)
Species:  Human
Tissue:  Bacterial membranes expressing human FZD1, rat brain and L-cell membranes
Response measured:  GDP/GTP exchange quantified by Eu-GTP/time resolved fluorescence
References:  11-12
Physiological Consequences of Altering Gene Expression
FZD1 receptor knockout mice are viable and normal.
Species:  Mouse
Tissue: 
Technique:  Transgenesis.
References:  18
Gene knockouts results in reduced fertility. FZD1 is required for normal female fertility and may act in part to regulate oocyte maturation and cumulus cell function
Species:  Mouse
Tissue:  Ovaries
Technique:  Gene knockouts
References:  13
FZD1–/– mice were healthy and fertile and exhibited no orofacial or cardiac anomalies. FZD1-/- did only result in detectable phenotypes when FZD2 and/or Vangl2 were reduced in simultaneously.
Species:  Mouse
Tissue:  Craniofacial/cardiac
Technique:  Gene knockouts
References:  22
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0002622 abnormal cochlear hair cell morphology PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0004406 abnormal cochlear hair cell number PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000266 abnormal heart morphology PMID: 20940229 
Fzd1tm1.1Nat|Fzd2+|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000266 abnormal heart morphology PMID: 20940229 
Fzd1+|Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1+,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000266 abnormal heart morphology PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000452 abnormal mouth morphology PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0004491 abnormal orientation of outer hair cell stereociliary bundles PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0009653 abnormal palate development PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000111 cleft palate PMID: 20940229 
Fzd1tm1.1Nat|Fzd2+|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000111 cleft palate PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0001575 cyanosis PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000284 double outlet heart right ventricle PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0009886 failure of palatal shelf elevation PMID: 20940229 
Fzd1tm1Dgen Fzd1tm1Dgen/Fzd1tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:1196625  MP:0002169 no abnormal phenotype detected
Fzd1+|Fzd1tm1.1Nat|Vangl2+|Vangl2Lp Fzd1tm1.1Nat/Fzd1+,Vangl2Lp/Vangl2+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA * LPT/LeJ
MGI:1196625  MGI:2135272  MP:0000929 open neural tube PMID: 20940229 
Fzd1+|Fzd1tm1.1Nat|Fzd2+|Fzd2tm1.1Nat|Vangl2+|Vangl2Lp Fzd1tm1.1Nat/Fzd1+,Fzd2tm1.1Nat/Fzd2+,Vangl2Lp/Vangl2+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA * LPT/LeJ
MGI:1196625  MGI:1888513  MGI:2135272  MP:0000929 open neural tube PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000273 overriding aorta PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0009888 palatal shelves fail to meet at midline PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0000088 short mandible PMID: 20940229 
Fzd1tm1.1Nat|Fzd2tm1.1Nat Fzd1tm1.1Nat/Fzd1tm1.1Nat,Fzd2tm1.1Nat/Fzd2tm1.1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA
MGI:1196625  MGI:1888513  MP:0010402 ventricular septal defect PMID: 20940229 
Fzd1+|Fzd1tm1.1Nat|Vangl2+|Vangl2Lp Fzd1tm1.1Nat/Fzd1+,Vangl2Lp/Vangl2+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA * LPT/LeJ
MGI:1196625  MGI:2135272  MP:0010402 ventricular septal defect PMID: 20940229 
Fzd1+|Fzd1tm1.1Nat|Fzd2+|Fzd2tm1.1Nat|Vangl2+|Vangl2Lp Fzd1tm1.1Nat/Fzd1+,Fzd2tm1.1Nat/Fzd2+,Vangl2Lp/Vangl2+
involves: 129S1/Sv * 129X1/SvJ * C57BL/6 * CBA * LPT/LeJ
MGI:1196625  MGI:1888513  MGI:2135272  MP:0010402 ventricular septal defect PMID: 20940229 
General Comments
The WNTs that are available in purified and active form for a pharmacological characterisation to date are WNT-3A and WNT-5A [17,20].

References

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1. Borello U, Buffa V, Sonnino C, Melchionna R, Vivarelli E, Cossu G. (1999) Differential expression of the Wnt putative receptors Frizzled during mouse somitogenesis. Mech Dev, 89: 173-177. [PMID:10559494]

2. Chan SD, Karpf DB, Fowlkes ME, Hooks M, Bradley MS, Vuong V, Bambino T, Liu MY, Arnaud CD, Strewler GJ. (1992) Two homologs of the Drosophila polarity gene frizzled (fz) are widely expressed in mammalian tissues. J Biol Chem, 267: 25202-25207. [PMID:1334084]

3. Chen M, Wang J, Lu J, Bond MC, Ren XR, Lyerly HK, Barak LS, Chen W. (2009) The anti-helminthic niclosamide inhibits Wnt/Frizzled1 signaling. Biochemistry, 48 (43): 10267-74. [PMID:19772353]

4. Daudet N, Ripoll C, Molès JP, Rebillard G. (2002) Expression of members of Wnt and Frizzled gene families in the postnatal rat cochlea. Brain Res Mol Brain Res, 105: 98-107. [PMID:12399112]

5. 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]

6. Fischer T, Guimera J, Wurst W, Prakash N. (2007) Distinct but redundant expression of the Frizzled Wnt receptor genes at signaling centers of the developing mouse brain. Neuroscience, 147: 693-711. [PMID:17582687]

7. Gao Y, Wang HY. (2006) Casein kinase 2 Is activated and essential for Wnt/beta-catenin signaling. J Biol Chem, 281: 18394-18400. [PMID:16672224]

8. Gao Y, Wang HY. (2007) Inositol Pentakisphosphate Mediates Wnt/beta-Catenin Signaling. J Biol Chem, 282: 26490-26502. [PMID:17595165]

9. Gazit A, Yaniv A, Bafico A, Pramila T, Igarashi M, Kitajewski J, Aaronson SA. (1999) Human frizzled 1 interacts with transforming Wnts to transduce a TCF dependent transcriptional response. Oncogene, 18: 5959-5966. [PMID:10557084]

10. Holcombe RF, Marsh JL, Waterman ML, Lin F, Milovanovic T, Truong T. (2002) Expression of Wnt ligands and Frizzled receptors in colonic mucosa and in colon carcinoma. Mol Pathol, 55: 220-226. [PMID:12147710]

11. Katanaev VL, Buestorf S. Frizzled Proteins are bona fide G Protein-Coupled Receptors. Accessed on 31/07/2014. Modified on 31/07/2014. Nature Precedings, http://precedings.nature.com/documents/2765/version/1

12. Koval A, Katanaev VL. (2011) Wnt3a stimulation elicits G-protein-coupled receptor properties of mammalian Frizzled proteins. Biochem. J., 433 (3): 435-40. [PMID:21128903]

13. Lapointe E, Boyer A, Rico C, Paquet M, Franco HL, Gossen J, DeMayo FJ, Richards JS, Boerboom D. (2012) FZD1 regulates cumulus expansion genes and is required for normal female fertility in mice. Biol. Reprod., 87 (5): 104. [PMID:22954793]

14. Liu T, Liu X, Wang H, Moon RT, Malbon CC. (1999) Activation of rat frizzled-1 promotes Wnt signaling and differentiation of mouse F9 teratocarcinoma cells via pathways that require Galpha(q) and Galpha(o) function. J Biol Chem, 274: 33539-33544. [PMID:10559239]

15. Neumann J, Schaale K, Farhat K, Endermann T, Ulmer AJ, Ehlers S, Reiling N. (2010) Frizzled1 is a marker of inflammatory macrophages, and its ligand Wnt3a is involved in reprogramming Mycobacterium tuberculosis-infected macrophages. FASEB J., 24 (11): 4599-612. [PMID:20667980]

16. Sagara N, Toda G, Hirai M, Terada M, Katoh M. (1998) Molecular cloning, differential expression, and chromosomal localization of human frizzled-1, frizzled-2, and frizzled-7. Biochem Biophys Res Commun, 252: 117-122. [PMID:9813155]

17. Schulte G, Bryja V, Rawal N, Castelo-Branco G, Sousa KM, Arenas E. (2005) Purified Wnt-5a increases differentiation of midbrain dopaminergic cells and dishevelled phosphorylation. J Neurochem, 92: 1550-1553. [PMID:15748172]

18. van Amerongen R, Berns A. (2006) Knockout mouse models to study Wnt signal transduction. Trends Genet, 22: 678-689. [PMID:17045694]

19. Wang Z, Shu W, Lu MM, Morrisey EE. (2005) Wnt7b activates canonical signaling in epithelial and vascular smooth muscle cells through interactions with Fzd1, Fzd10, and LRP5. Mol Cell Biol, 25: 5022-5030. [PMID:15923619]

20. Willert K, Brown JD, Danenberg E, Duncan AW, Weissman IL, Reya T, Yates JR, Nusse R. (2003) Wnt proteins are lipid-modified and can act as stem cell growth factors. Nature, 423: 448-452. [PMID:12717451]

21. Xu L, Tan L, Goldring MB, Olsen BR, Li Y. (2001) Expression of frizzled genes in mouse costochondral chondrocytes. Matrix Biol, 20: 147-151. [PMID:11334716]

22. Yu H, Smallwood PM, Wang Y, Vidaltamayo R, Reed R, Nathans J. (2010) Frizzled 1 and frizzled 2 genes function in palate, ventricular septum and neural tube closure: general implications for tissue fusion processes. Development, 137 (21): 3707-17. [PMID:20940229]

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: FZD1. Last modified on 14/07/2015. Accessed on 13/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=229.