FZD<sub>8</sub> | Class Frizzled GPCRs | IUPHAR/BPS Guide to PHARMACOLOGY

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FZD8

Target id: 236

Nomenclature: FZD8

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 FZD8 in GtoImmuPdb

Gene and Protein Information
Frizzled family G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 694 10p11.22 FZD8 frizzled class receptor 8 13
Mouse 7 685 18 A1; 18 4.91 cM Fzd8 frizzled class receptor 8
Rat 7 684 17q12.1 Fzd8 frizzled class receptor 8
Previous and Unofficial Names
frizzled family receptor 8 | Fz8
Database Links
CATH/Gene3D
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Natural/Endogenous Ligands
Wnt
Agonist Comments
FZDs are receptors for WNT proteins. Until now FZD8 has been proven to bind to WNT-2 [2] WNT-3A [9,11] WNT-9B [12] and Xenopus WNT-8 (XWNT-8 or mini-WNT) [6]. For more detail information see [3].
Primary Transduction Mechanisms
Transducer Effector/Response
G protein (identity unknown) Other - See Comments
Comments:  Involvement of G proteins likely.

Effector/response: β-catenin translocation to the nucleus shown by TOPflash activity after WNT-9B and WNT-2 activation of FZD8 ([12] and [2] respectively), although it is also reported that FZD8 receptor activation will inhibit β-catenin signaling [10,16].
References: 
Tissue Distribution
Kidney
Species:  Human
Technique:  Immunohistochemistry and RNA expression
References:  17
Crypt epithelial preparations and intestinal myofibroblasts isolated from human intestinal mucosal samples.
Species:  Human
Technique:  PCR-array
References:  5
Adult kidney, heart, pancreas, skeletal muscle, and in fetal kidney and brain
Species:  Human
Technique:  RT-PCR
References:  13
Thyroid gland
Species:  Human
Technique:  Immunohistochemistry and RNA expression
References:  17
Lung
Species:  Human
Technique:  Immunohistochemistry and RNA expression
References:  17
K562 cells, hematopoietic stem cells
Species:  Human
Technique:  RNAi-based synthetic lethal screen
References:  4
Mesenchymal stem cells
Species:  Human
Technique:  qRT-PCR
References:  10
Developing kidney
Species:  Mouse
Technique:  Expression of lacZ reporter
References:  20
Primary hematopoietic stem cells
Species:  Mouse
Technique:  Immunocytochemistry
References:  16
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
WNT-9B can activate TOPflash activity through FZD8 in HEK 293 cells
Species:  Human
Tissue:  HEK293 cells
Response measured:  TOPflash activity, β-catenin signaling
References:  12
WNT-2 activates TCF transcriptional activity in 293T, 293 and NSCLC cell line A549 overexpressing FZD8
Species:  Human
Tissue:  293T, 293 and NSCLC cell line A549
Response measured:  TOPflash activity, β-catenin signaling
References:  2
FZD8 (together with Flamingo), maintains haematopoietic stem cells in a long-term quiescent state through their cooperation in the osteoblast niche. Mechanism is based on the suppression of Ca2+-NFAT-IFNγ (calcium-nuclear factor of activated T-cell-IFNγ) pathway through the CDC 42-PAK1-CK1α pathway.
Species:  Mouse
Tissue:  Primary haematopoietic stem cells
Response measured:  Suppression of Ca2+-NFAT-IFNγ pathway
References:  16
RNAi against FZD8 and also FZD8 overexpression results in an enhanced Wnt/β-catenin signaling in human mesenchymal stem cells
Species:  Human
Tissue:  Mesenchymal stem cells
Response measured:  TOPflash activity, β-catenin signaling
References:  10
Functional Assay Comments
Pinpointing one of the FZD isoforms in relationship to functional assays is compromised due to the high endogenous expression of various FZD isoforms in many cellular systems.
Physiological Functions
FZD8 (together with Flamingo), maintains haematopoietic stem cells in a long-term quiescent state through their cooperation in the osteoblast niche
Species:  Mouse
Tissue:  Primary haematopoietic stem cells
References:  16
Physiological Consequences of Altering Gene Expression
Renal hypoplasia through decreased growth, branching and cell proliferation in Fz4−/−;Fz8−/− mice
Species:  Mouse
Tissue:  Kidney
Technique:  Gene knockouts
References:  20
Physiological Consequences of Altering Gene Expression Comments
No abnormal phenotype was detected in whole animal knockout mice [18].
Phenotypes, Alleles and Disease Models Mouse data from MGI

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Allele Composition & genetic background Accession Phenotype Id Phenotype Reference
Fzd8tm1Dgen Fzd8tm1Dgen/Fzd8tm1Dgen
involves: 129P2/OlaHsd * C57BL/6
MGI:108460  MP:0002169 no abnormal phenotype detected
Clinically-Relevant Mutations and Pathophysiology
Disease:  Acute myeloid leukemia
Synonyms: Acute myelogenous leukemia
Disease Ontology: DOID:9119
OMIM: 601626
Orphanet: ORPHA519
References:  15
Disease:  B-cell non-hodgkin lymphoma
Orphanet: ORPHA171915
References:  1
Disease:  Interstitial cystitis
Disease Ontology: DOID:13949
References:  8
Disease:  Lung cancer
Disease Ontology: DOID:1324
OMIM: 211980
References:  2,19
Disease:  Medulloblastoma
Disease Ontology: DOID:3858
OMIM: 155255
References:  14
Disease:  Renal cell carcinoma
Disease Ontology: DOID:4450
References:  7

References

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1. Bethge N, Honne H, Hilden V, Trøen G, Eknæs M, Liestøl K, Holte H, Delabie J, Smeland EB, Lind GE. (2013) Identification of highly methylated genes across various types of B-cell non-hodgkin lymphoma. PLoS ONE, 8 (11): e79602. [PMID:24260260]

2. Bravo DT, Yang YL, Kuchenbecker K, Hung MS, Xu Z, Jablons DM, You L. (2013) Frizzled-8 receptor is activated by the Wnt-2 ligand in non-small cell lung cancer. BMC Cancer, 13: 316. [PMID:23815780]

3. 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]

4. Gregory MA, Phang TL, Neviani P, Alvarez-Calderon F, Eide CA, O'Hare T, Zaberezhnyy V, Williams RT, Druker BJ, Perrotti D et al.. (2010) Wnt/Ca2+/NFAT signaling maintains survival of Ph+ leukemia cells upon inhibition of Bcr-Abl. Cancer Cell, 18 (1): 74-87. [PMID:20609354]

5. Hughes KR, Sablitzky F, Mahida YR. (2011) Expression profiling of Wnt family of genes in normal and inflammatory bowel disease primary human intestinal myofibroblasts and normal human colonic crypt epithelial cells. Inflamm. Bowel Dis., 17 (1): 213-20. [PMID:20848536]

6. Janda CY, Waghray D, Levin AM, Thomas C, Garcia KC. (2012) Structural basis of Wnt recognition by Frizzled. Science, 337 (6090): 59-64. [PMID:22653731]

7. Janssens N, Andries L, Janicot M, Perera T, Bakker A. (2004) Alteration of frizzled expression in renal cell carcinoma. Tumour Biol., 25 (4): 161-71. [PMID:15557753]

8. Keay SK, Szekely Z, Conrads TP, Veenstra TD, Barchi Jr JJ, Zhang CO, Koch KR, Michejda CJ. (2004) An antiproliferative factor from interstitial cystitis patients is a frizzled 8 protein-related sialoglycopeptide. Proc. Natl. Acad. Sci. U.S.A., 101 (32): 11803-8. [PMID:15282374]

9. Kemp CR, Willems E, Wawrzak D, Hendrickx M, Agbor Agbor T, Leyns L. (2007) Expression of Frizzled5, Frizzled7, and Frizzled10 during early mouse development and interactions with canonical Wnt signaling. Dev. Dyn., 236 (7): 2011-9. [PMID:17576136]

10. Kolben T, Peröbner I, Fernsebner K, Lechner F, Geissler C, Ruiz-Heinrich L, Capovilla S, Jochum M, Neth P. (2012) Dissecting the impact of Frizzled receptors in Wnt/β-catenin signaling of human mesenchymal stem cells. Biol. Chem., 393 (12): 1433-47. [PMID:23152409]

11. Kumar S, Zigman M, Patel TR, Trageser B, Gross JC, Rahm K, Boutros M, Gradl D, Steinbeisser H, Holstein T et al.. (2014) Molecular dissection of Wnt3a-Frizzled8 interaction reveals essential and modulatory determinants of Wnt signaling activity. BMC Biol., 12 (1): 44. [PMID:24885675]

12. Liu C, Wang Y, Smallwood PM, Nathans J. (2008) An essential role for Frizzled5 in neuronal survival in the parafascicular nucleus of the thalamus. J. Neurosci., 28 (22): 5641-53. [PMID:18509025]

13. Saitoh T, Hirai M, Katoh M. (2001) Molecular cloning and characterization of human Frizzled-8 gene on chromosome 10p11.2. Int. J. Oncol., 18 (5): 991-6. [PMID:11295046]

14. Salsano E, Paterra R, Figus M, Menghi F, Maderna E, Pollo B, Solero CL, Massimi L, Finocchiaro G. (2012) Expression profile of frizzled receptors in human medulloblastomas. J. Neurooncol., 106 (2): 271-80. [PMID:21850537]

15. Sonnet M, Claus R, Becker N, Zucknick M, Petersen J, Lipka DB, Oakes CC, Andrulis M, Lier A, Milsom MD et al.. (2014) Early aberrant DNA methylation events in a mouse model of acute myeloid leukemia. Genome Med, 6 (4): 34. [PMID:24944583]

16. Sugimura R, He XC, Venkatraman A, Arai F, Box A, Semerad C, Haug JS, Peng L, Zhong XB, Suda T et al.. (2012) Noncanonical Wnt signaling maintains hematopoietic stem cells in the niche. Cell, 150 (2): 351-65. [PMID:22817897]

17. Uhlen M, Oksvold P, Fagerberg L, Lundberg E, Jonasson K, Forsberg M, Zwahlen M, Kampf C, Wester K, Hober S et al.. (2010) Towards a knowledge-based Human Protein Atlas. Nat. Biotechnol., 28 (12): 1248-50. [PMID:21139605]

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

19. Wang HQ, Xu ML, Ma J, Zhang Y, Xie CH. (2012) Frizzled-8 as a putative therapeutic target in human lung cancer. Biochem. Biophys. Res. Commun., 417 (1): 62-6. [PMID:22138402]

20. Ye X, Wang Y, Rattner A, Nathans J. (2011) Genetic mosaic analysis reveals a major role for frizzled 4 and frizzled 8 in controlling ureteric growth in the developing kidney. Development, 138 (6): 1161-72. [PMID:21343368]

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: FZD8. Last modified on 23/02/2015. Accessed on 21/11/2018. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=236.