Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR committee on Frizzled receptors, [10]), are GPCR originally identified in Drosophila [4], which are highly conserved across species. FZD are activated by WNTs, which are lipidated, cysteine-rich glycoprotein hormones with fundamental functions in ontogeny and tissue homeostatis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription factor β-catenin (ENSG00000168036) or being β-catenin-independent (often referred to as canonical vs non-canonical WNT/FZD signaling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors (LRP 5, ENSG00000162337 and LRP6, ENSG00000070018), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin. β-Catenin, in turn, modifies gene transcription in concert with TCF/LEF transcription factors. β-Catenin-independent FZD signalling is far more complex with regard to the diversity of the activated pathways. WNT/FZD signalling can lead to the activation of pertussis toxin-sensitive heterotrimeric G proteins [8], the elevation of intracellular calcium [11], activation of cGMP-specific PDE6 [1] and elevation of cAMP [6]. FZD signalling can also occur through Dishevelled phosphoproteins (ENSFM00250000001001) to RAC-1 and JNK, as well as Rho and ROCK kinases. As with other GPCRs, members of the Frizzled family are functionally dependent on the β-arrestin scaffolding protein for internalization [5], β-catenin-dependent [2] and -independent [3,9] signalling. The pattern of cell signalling is complicated by the presence of additional ligands which can enhance (norrin or R-spondin) or inhibit FZD function [secreted Frizzled-related proteins [sFRP], Wnt-inhibitory factor [WIF], SOST or Dickkopf), as well as modulatory proteins with positive (Ryk, ENSG00000163785; ROR1, ENSG00000185483 and ROR2, ENSG00000169071) and negative (Kremen) regulatory features, which may also function as independent signalling proteins.

There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration–response relationships [7].

Ligands associated with FZD signalling

Angers, S; Moon, RT. (2009) Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol., 10 (7): 468-77. [PMID:19536106]

Blankesteijn, WM; van de Schans, VA; ter Horst, P; Smits, JF. (2008) The Wnt/frizzled/GSK-3 beta pathway: a novel therapeutic target for cardiac hypertrophy. Trends Pharmacol. Sci., 29 (4): 175-80. [PMID:18342376]

Chien, AJ; Moon, RT. (2007) WNTS and WNT receptors as therapeutic tools and targets in human disease processes. Front. Biosci., 12: 448-57. [PMID:17127309]

Egger-Adam, D; Katanaev, VL. (2008) Trimeric G protein-dependent signaling by Frizzled receptors in animal development. Front. Biosci., 13: 4740-55. [PMID:18508542]

Jin, T; George Fantus, I; Sun, J. (2008) Wnt and beyond Wnt: multiple mechanisms control the transcriptional property of beta-catenin. Cell. Signal., 20 (10): 1697-704. [PMID:18555664]

Kikuchi, A., Yamamoto, H. and Kishida, S. (2007) Multiplicity of the interactions of Wnt proteins and their receptors. Cell Signal, 19: 659-671. [PMID:17188462]

Kikuchi, A; Yamamoto, H; Sato, A. (2009) Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol., 19 (3): 119-29. [PMID:19208479]

Luo, J., Chen, J., Deng, Z. L., Luo, X., Song, W. X., Sharff, K. A., Tang, N., Haydon, R. C., Luu, H. H. and He, T. C. (2007) Wnt signaling and human diseases: what are the therapeutic implications?. Lab Invest, 87: 97-103. [PMID:17211410]

Maiese, K; Li, F; Chong, ZZ; Shang, YC. (2008) The Wnt signaling pathway: aging gracefully as a protectionist?. Pharmacol. Ther., 118 (1): 58-81. [PMID:18313758]

Salinas, PC; Zou, Y. (2008) Wnt signaling in neural circuit assembly. Annu. Rev. Neurosci., 31: 339-58. [PMID:18558859]

Schulte, G. (2010) International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors. Pharmacol. Rev., 62 (4): 632-67. [PMID:21079039]

Schulte, G. and Bryja, V. (2007) The Frizzled family of unconventional G-protein-coupled receptors. Trends Pharmacol Sci, 28 (10): 518-25. [PMID:17884187]

Schulte, G; Schambony, A; Bryja, V. (2010) beta-Arrestins - scaffolds and signalling elements essential for WNT/Frizzled signalling pathways?. Br. J. Pharmacol., 159 (5): 1051-8. [PMID:19888962]

Seifert, JR; Mlodzik, M. (2007) Frizzled/PCP signalling: a conserved mechanism regulating cell polarity and directed motility. Nat. Rev. Genet., 8 (2): 126-38. [PMID:17230199]

Speese, SD; Budnik, V. (2007) Wnts: up-and-coming at the synapse. Trends Neurosci., 30 (6): 268-75. [PMID:17467065]

Staal, FJ; Luis, TC; Tiemessen, MM. (2008) WNT signalling in the immune system: WNT is spreading its wings. Nat. Rev. Immunol., 8 (8): 581-93. [PMID:18617885]

van de Schans, VA; Smits, JF; Blankesteijn, WM. (2008) The Wnt/frizzled pathway in cardiovascular development and disease: friend or foe?. Eur. J. Pharmacol., 585 (2-3): 338-45. [PMID:18417121]

1. Ahumada, A., Slusarski, D. C., Liu, X., Moon, R. T., Malbon, C. C. and Wang, H. Y. (2002) Signaling of rat Frizzled-2 through phosphodiesterase and cyclic GMP. Science, 298: 2006-2010. [PMID:12471263]

2. Bryja, V; Gradl, D; Schambony, A; Arenas, E; Schulte, G. (2007) Beta-arrestin is a necessary component of Wnt/beta-catenin signaling in vitro and in vivo. Proc. Natl. Acad. Sci. U.S.A., 104 (16): 6690-5. [PMID:17426148]

3. Bryja, V; Schambony, A; Cajánek, L; Dominguez, I; Arenas, E; Schulte, G. (2008) Beta-arrestin and casein kinase 1/2 define distinct branches of non-canonical WNT signalling pathways. EMBO Rep., 9 (12): 1244-50. [PMID:18953287]

4. Chan, S. D., Karpf, D. B., Fowlkes, M. E., Hooks, M., Bradley, M. S., Vuong, V., Bambino, T., Liu, M. Y., Arnaud, C. D. and Strewler, G. J. (1992) Two homologs of the Drosophila polarity gene frizzled (fz) are widely expressed in mammalian tissues. J Biol Chem, 267: 25202-25207. [PMID:1334084]

5. Chen, W; Kirkbride, KC; How, T; Nelson, CD; Mo, J; Frederick, JP; Wang, XF; Lefkowitz, RJ; Blobe, GC. (2003) Beta-arrestin 2 mediates endocytosis of type III TGF-beta receptor and down-regulation of its signaling. Science, 301 (5638): 1394-7. [PMID:12958365]

6. 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]

7. Kikuchi, A; Yamamoto, H; Sato, A. (2009) Selective activation mechanisms of Wnt signaling pathways. Trends Cell Biol., 19 (3): 119-29. [PMID:19208479]

8. Kilander, MB; Dijksterhuis, JP; Ganji, RS; Bryja, V; Schulte, G. (2011) WNT-5A stimulates the GDP/GTP exchange at pertussis toxin-sensitive heterotrimeric G proteins. Cell. Signal., 23 (3): 550-4. [PMID:21070854]

9. Kim, GH; Han, JK. (2007) Essential role for beta-arrestin 2 in the regulation of Xenopus convergent extension movements. EMBO J., 26 (10): 2513-26. [PMID:17476309]

10. Schulte, G. (2010) International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors. Pharmacol. Rev., 62 (4): 632-67. [PMID:21079039]

11. Slusarski, DC; Corces, VG; Moon, RT. (1997) Interaction of Wnt and a Frizzled homologue triggers G-protein-linked phosphatidylinositol signalling. Nature, 390 (6658): 410-3. [PMID:9389482]