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FZD8

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Target not currently curated in GtoImmuPdb

Target id: 236

Nomenclature: FZD8

Family: Class Frizzled GPCRs

Gene and Protein Information Click here for help
Frizzled family G protein-coupled receptor
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 7 694 10p11.21 FZD8 frizzled class receptor 8 15
Mouse 7 685 18 4.91 cM Fzd8 frizzled class receptor 8
Rat 7 684 17q12.1 Fzd8 frizzled class receptor 8
Previous and Unofficial Names Click here for help
frizzled family receptor 8 | Fz8
Database Links Click here for help
Alphafold
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Carbamazepine binds Frizzled8.
PDB Id:  6TFB
Ligand:  carbamazepine
Resolution:  1.68Å
Species:  Mouse
References:  23
Natural/Endogenous Ligands Click here for help
Wnt

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Agonist Comments
FZDs are receptors for WNT proteins. Until now FZD8 has been proven to bind to WNT-2 [2] WNT-3A [11,13] WNT-9B [14] and Xenopus WNT-8 (XWNT-8 or mini-WNT) [8]. For more detail information see [4].
Antagonist Comments
FZD8-Fc/OMP-54F28 is a FZD8 antagonist [3].
Allosteric Modulators
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
carbamazepine Small molecule or natural product Approved drug Ligand has a PDB structure Hs Negative 4.8 pKd 23
pKd 4.8 (Kd 1.68x10-5 M) [23]
Description: Binding affinity for FZD8 cysteine-rich domain (CRD) by SPR analysis.
Antibodies
Key to terms and symbols Click column headers to sort
Antibody Sp. Action Value Parameter Reference
vantictumab Peptide Click here for species-specific activity table Hs Antagonist ~8.0 pIC50 6
pIC50 ~8.0 (IC50 ~1x10-8 M) [6]
Immuno Process Associations
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes, IEA only
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GO:0033077 T cell differentiation in thymus IEA
Immuno Process:  Immune system development
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0033077 T cell differentiation in thymus IEA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0033077 T cell differentiation in thymus IEA
Primary Transduction Mechanisms Click here for help
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 ([14] and [2] respectively), although it is also reported that FZD8 receptor activation will inhibit β-catenin signaling [12,18].
References: 
Tissue Distribution Click here for help
Kidney
Species:  Human
Technique:  Immunohistochemistry and RNA expression
References:  19
Crypt epithelial preparations and intestinal myofibroblasts isolated from human intestinal mucosal samples.
Species:  Human
Technique:  PCR-array
References:  7
Adult kidney, heart, pancreas, skeletal muscle, and in fetal kidney and brain
Species:  Human
Technique:  RT-PCR
References:  15
Thyroid gland
Species:  Human
Technique:  Immunohistochemistry and RNA expression
References:  19
Lung
Species:  Human
Technique:  Immunohistochemistry and RNA expression
References:  19
K562 cells, hematopoietic stem cells
Species:  Human
Technique:  RNAi-based synthetic lethal screen
References:  5
Mesenchymal stem cells
Species:  Human
Technique:  qRT-PCR
References:  12
Developing kidney
Species:  Mouse
Technique:  Expression of lacZ reporter
References:  22
Primary hematopoietic stem cells
Species:  Mouse
Technique:  Immunocytochemistry
References:  18
Expression Datasets Click here for help

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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 Click here for help
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:  14
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:  18
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:  12
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 Click here for help
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:  18
Physiological Consequences of Altering Gene Expression Click here for help
Renal hypoplasia through decreased growth, branching and cell proliferation in Fz4−/−;Fz8−/− mice
Species:  Mouse
Tissue:  Kidney
Technique:  Gene knockouts
References:  22
Physiological Consequences of Altering Gene Expression Comments
No abnormal phenotype was detected in whole animal knockout mice [20].
Phenotypes, Alleles and Disease Models Click here for help 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 Click here for help
Disease:  Acute myeloid leukemia
Synonyms: Acute myelogenous leukemia
Disease Ontology: DOID:9119
OMIM: 601626
Orphanet: ORPHA519
References:  17
Disease:  B-cell non-hodgkin lymphoma
Orphanet: ORPHA171915
References:  1
Disease:  Interstitial cystitis
Disease Ontology: DOID:13949
References:  10
Disease:  Lung cancer
Disease Ontology: DOID:1324
OMIM: 211980
References:  2,21
Disease:  Medulloblastoma
Disease Ontology: DOID:3858
OMIM: 155255
References:  16
Disease:  Renal cell carcinoma
Disease Ontology: DOID:4450
References:  9

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. DeAlmeida VI, Miao L, Ernst JA, Koeppen H, Polakis P, Rubinfeld B. (2007) The soluble wnt receptor Frizzled8CRD-hFc inhibits the growth of teratocarcinomas in vivo. Cancer Res, 67 (11): 5371-9. [PMID:17545618]

4. 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]

5. 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]

6. Gurney A, Axelrod F, Bond CJ, Cain J, Chartier C, Donigan L, Fischer M, Chaudhari A, Ji M, Kapoun AM et al.. (2012) Wnt pathway inhibition via the targeting of Frizzled receptors results in decreased growth and tumorigenicity of human tumors. Proc Natl Acad Sci USA, 109 (29): 11717-22. [PMID:22753465]

7. 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]

8. 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]

9. 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]

10. 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 USA, 101 (32): 11803-8. [PMID:15282374]

11. 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]

12. 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]

13. 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]

14. 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]

15. 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]

16. 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]

17. 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]

18. 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]

19. 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]

20. van Amerongen R, Berns A. (2006) Knockout mouse models to study Wnt signal transduction. Trends Genet, 22 (12): 678-89. [PMID:17045694]

21. 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]

22. 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]

23. Zhao Y, Ren J, Hillier J, Lu W, Jones EY. (2020) Antiepileptic Drug Carbamazepine Binds to a Novel Pocket on the Wnt Receptor Frizzled-8. J Med Chem, 63 (6): 3252-3260. [PMID:32049522]

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