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FZD6

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Target not currently curated in GtoImmuPdb

Target id: 234

Nomenclature: FZD6

Family: Class Frizzled GPCRs

Contents:

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 7 706 8q22.3 FZD6 frizzled class receptor 6 19
Mouse 7 709 15 15.22 cM Fzd6 frizzled class receptor 6 23
Rat 7 710 7q22 Fzd6 frizzled class receptor 6 3
Previous and Unofficial Names Click here for help
Fz6 | frizzled family receptor 6
Database Links Click here for help
Alphafold O60353 (Hs), Q61089 (Mm)
CATH/Gene3D 1.10.2000.10
Ensembl Gene ENSG00000164930 (Hs), ENSMUSG00000022297 (Mm), ENSRNOG00000004660 (Rn)
Entrez Gene 8323 (Hs), 14368 (Mm), 282581 (Rn)
Human Protein Atlas ENSG00000164930 (Hs)
KEGG Gene hsa:8323 (Hs), mmu:14368 (Mm), rno:282581 (Rn)
OMIM 603409 (Hs)
Orphanet ORPHA280659 (Hs)
Pharos O60353 (Hs)
RefSeq Nucleotide NM_003506 (Hs), NM_008056 (Mm), NM_001130536 (Rn)
RefSeq Protein NP_003497 (Hs), NP_032082 (Mm), NP_001124008 (Rn)
UniProtKB O60353 (Hs), Q61089 (Mm)
Wikipedia FZD6 (Hs)
Natural/Endogenous Ligands Click here for help
Wnt-4 {Sp: Human}
Wnt-5a {Sp: Human}
Wnt-3a {Sp: Human}

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Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
SAG1.3 Small molecule or natural product Hs Partial agonist 5.6 pKd 12
⤷ pKd 5.6 (Kd 2.51x10-6 M) [12]
Description: Determined in a displacement NanoBRET assay using BODIPY–cyclopamine and nanoluciferase (Nluc)-tagged FZD6, in cells with CRISPR/Cas9 disabled SMO expression.
Wnt-4 {Sp: Human} Peptide Ligand is endogenous in the given species Hs Agonist - - 8,13
⤷ [8,13]
Wnt-5a {Sp: Human} Peptide Ligand is endogenous in the given species Hs Agonist - - 5
⤷ [5]
Wnt-3a {Sp: Human} Peptide Ligand is endogenous in the given species Hs Agonist - - 5,11
⤷ [5,11]
Agonist Comments
FZDs are receptors for WNT proteins. Until now FZD6 has been proven to bind to WNT 3A, 4, 5A, 5B, and 7A. For more detail information see [4].
Primary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family
Gq/G11 family
G protein independent mechanism
Comments:  FZD6-mediated Gαo activation in an E. coli reconstitution system has been shown [9]. FZD6 is precoupled to Gαi and Gαq [10]. Transduction is, β-catenin-dependent and β-catenin-independent WNT, dependent on DVL [1].
References:  1
Secondary Transduction Mechanisms Click here for help
Transducer Effector/Response
Gi/Go family Other - See Comments
Comments:  GTPγS-binding
References:  11
Tissue Distribution Click here for help
Pituitary glands/pituitary adenomas
Species:  Human
Technique:  Immunocytochemistry
References:  14
Hematopoietic progenitor cells
Species:  Mouse
Technique:  RT-PCR
References:  8
Dorsal midbrain
Species:  Mouse
Technique:  RT-PCR
References:  16
Lung
Species:  Mouse
Technique:  Microarray analysis
References:  20
Thymus
Species:  Mouse
Technique:  RT-PCR
References:  21
E.8.5 - notochord; later: metencephalon, isthmus, midbrain, optic and otic placode, branchial arches, conjunction edges of the diencephalon with the telencephalic vesicles; E10.5 - rostro-lateral edge of the newly formed somites; ectoderm overlapping the dermomyotome; dorso-medial lip of the dorsomyotome; ectoderm in the forelimb; metanephric duct; gut; notochord;
Species:  Mouse
Technique:  Whole mount in situ hybridisation
References:  2
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 Assay Comments
FZD6 has been identified as a negative regulator of the β-catenin dependent signalling cascade [6].
Physiological Functions Click here for help
Enhancement of hematopoietic progenitor cells expansion
Species:  Mouse
Tissue:  hematopoietic progenitor cells
References:  8
Regulation of nail development
Species:  Human
Tissue:  finger/toe tips; epidermis
References:  5
Regulation of hair follicle orientation; ablation of FZD6 gene causes hair whorls in mice
Species:  Mouse
Tissue:  Skin
References:  7
FZD6 is upregulated by β-carotene in the lung
Species:  Mouse
Tissue:  Lung
References:  20
FZD6 is a critical component in the development of B cell chronic lymphocytic leukemia
Species:  Mouse
Tissue:  B cells.
References:  24
Planar cell polarity effects in the inner ear in FZD3/FZD6 double knock out mice
Species:  Mouse
Tissue: 
References:  22
Physiological Consequences of Altering Gene Expression Click here for help
FZD6 controls hair patterning in mice. Gene knockouts result in hair and bristle patterning defect.
Species:  Mouse
Tissue:  Hair
Technique:  Gene knockouts
References:  7
FZD3 and FZD6 deficiency results in a severe midbrain morphogenesis defect.
Species:  Mouse
Tissue:  Midbrain
Technique:  Gene knockouts
References:  18
Ablation of Fzd6 gene causes hair whorles, claw defects in mouse
Species:  Mouse
Tissue:  in vivo
Technique:  Transgenesis
References:  5,7
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
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 
Fzd6tm1Nat Fzd6tm1Nat/Fzd6tm1Nat
129		 MGI:108474  MP:0000383 abnormal hair follicle orientation PMID: 15169958 
Fzd6tm1Nat Fzd6tm1Nat/Fzd6tm1Nat
involves: 129 * C57BL/6		 MGI:108474  MP:0000383 abnormal hair follicle orientation PMID: 15169958 
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|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|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:108474  MGI:108476  MP:0003051 curly tail PMID: 16495441 
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|Fzd6tm1Nat Fzd3tm1Nat/Fzd3tm1Nat,Fzd6tm1Nat/Fzd6tm1Nat
involves: 129S1/Sv * 129X1/SvJ * C57BL/6		 MGI:108474  MGI:108476  MP:0002058 neonatal lethality PMID: 16495441 
Fzd6tm1Dgen Fzd6tm1Dgen/Fzd6tm1Dgen
involves: 129P2/OlaHsd * C57BL/6		 MGI:108474  MP:0002169 no abnormal phenotype detected
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 
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Nail disorder, nonsyndromic congenital, 10; NDNC10
Synonyms: Autosomal-recessive nail dysplasia [Orphanet: ORPHA280654]
OMIM: 614157
Orphanet: ORPHA280654
References:  5
Click column headers to sort
Type Species Amino acid change Nucleotide change Description Reference
Missense Human G422A 17
Missense Human R511C c.1531C>T C terminus; causes isolated autosomal-recessive nail dysplasia 5
Nonsense Human E584X c.1750G>T C terminus; causes isolated autosomal-recessive nail dysplasia 5,15

References

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1. Borello U, Berarducci B, Murphy P, Bajard L, Buffa V, Piccolo S, Buckingham M, Cossu G. (2006) The Wnt/beta-catenin pathway regulates Gli-mediated Myf5 expression during somitogenesis. Development, 133 (18): 3723-32. [PMID:16936075]

2. 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 (1-2): 173-7. [PMID:10559494]

3. 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 (1-2): 98-107. [PMID:12399112]

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. Fröjmark AS, Schuster J, Sobol M, Entesarian M, Kilander MB, Gabrikova D, Nawaz S, Baig SM, Schulte G, Klar J et al.. (2011) Mutations in frizzled 6 cause isolated autosomal-recessive nail dysplasia. Am J Hum Genet, 88 (6): 852-60. [PMID:21665003]

6. Golan T, Yaniv A, Bafico A, Liu G, Gazit A. (2004) The human Frizzled 6 (HFz6) acts as a negative regulator of the canonical Wnt. beta-catenin signaling cascade. J Biol Chem, 279 (15): 14879-88. [PMID:14747478]

7. Guo N, Hawkins C, Nathans J. (2004) Frizzled6 controls hair patterning in mice. Proc Natl Acad Sci USA, 101 (25): 9277-81. [PMID:15169958]

8. Heinonen KM, Vanegas JR, Lew D, Krosl J, Perreault C. (2011) Wnt4 enhances murine hematopoietic progenitor cell expansion through a planar cell polarity-like pathway. PLoS ONE, 6 (4): e19279. [PMID:21541287]

9. 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

10. Kilander MB, Petersen J, Andressen KW, Ganji RS, Levy FO, Schuster J, Dahl N, Bryja V, Schulte G. (2014) Disheveled regulates precoupling of heterotrimeric G proteins to Frizzled 6. FASEB J, 28 (5): 2293-305. [PMID:24500924]

11. 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]

12. Kozielewicz P, Turku A, Bowin CF, Petersen J, Valnohova J, Cañizal MCA, Ono Y, Inoue A, Hoffmann C, Schulte G. (2020) Structural insight into small molecule action on Frizzleds. Nat Commun, 11 (1): 414. [PMID:31964872]

13. Lyons JP, Mueller UW, Ji H, Everett C, Fang X, Hsieh JC, Barth AM, McCrea PD. (2004) Wnt-4 activates the canonical beta-catenin-mediated Wnt pathway and binds Frizzled-6 CRD: functional implications of Wnt/beta-catenin activity in kidney epithelial cells. Exp Cell Res, 298 (2): 369-87. [PMID:15265686]

14. Miyakoshi T, Takei M, Kajiya H, Egashira N, Takekoshi S, Teramoto A, Osamura RY. (2008) Expression of Wnt4 in human pituitary adenomas regulates activation of the beta-catenin-independent pathway. Endocr Pathol, 19 (4): 261-73. [PMID:19034702]

15. Naz G, Pasternack SM, Perrin C, Mattheisen M, Refke M, Khan S, Gul A, Simons M, Ahmad W, Betz RC. (2012) FZD6 encoding the Wnt receptor frizzled 6 is mutated in autosomal-recessive nail dysplasia. Br J Dermatol, 166 (5): 1088-94. [PMID:22211385]

16. Rawal N, Castelo-Branco G, Sousa KM, Kele J, Kobayashi K, Okano H, Arenas E. (2006) Dynamic temporal and cell type-specific expression of Wnt signaling components in the developing midbrain. Exp Cell Res, 312 (9): 1626-36. [PMID:16510140]

17. Raza SI, Muhammad N, Khan S, Ahmad W. (2013) A novel missense mutation in the gene FZD6 underlies autosomal recessive nail dysplasia. Br J Dermatol, 168 (2): 422-5. [PMID:22861124]

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. Tokuhara M, Hirai M, Atomi Y, Terada M, Katoh M. (1998) Molecular cloning of human Frizzled-6. Biochem Biophys Res Commun, 243 (2): 622-7. [PMID:9480858]

20. van Helden YG, Godschalk RW, Heil SG, Bunschoten A, Hessel S, Amengual J, Bonet ML, von Lintig J, van Schooten FJ, Keijer J. (2010) Downregulation of Fzd6 and Cthrc1 and upregulation of olfactory receptors and protocadherins by dietary beta-carotene in lungs of Bcmo1-/- mice. Carcinogenesis, 31 (8): 1329-37. [PMID:20472610]

21. Varecza Z, Kvell K, Talabér G, Miskei G, Csongei V, Bartis D, Anderson G, Jenkinson EJ, Pongracz JE. (2011) Multiple suppression pathways of canonical Wnt signalling control thymic epithelial senescence. Mech Ageing Dev, 132 (5): 249-56. [PMID:21549744]

22. 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 (8): 2147-56. [PMID:16495441]

23. 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 (8): 4468-76. [PMID:8626800]

24. Wu QL, Zierold C, Ranheim EA. (2009) Dysregulation of Frizzled 6 is a critical component of B-cell leukemogenesis in a mouse model of chronic lymphocytic leukemia. Blood, 113 (13): 3031-9. [PMID:19179304]

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