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Class Frizzled GPCRs C

Unless otherwise stated all data on this page refer to the human proteins. Gene information is provided for human (Hs), mouse (Mm) and rat (Rn).

Overview

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Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [43]), are GPCRs originally identified in Drosophila [7], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in the Hedgehog signaling pathway [43]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [3,19,45]. While SMO itself is bound by sterols and oxysterols [10,26], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signalling was initially divided into two pathways, being either dependent on the accumulation of the transcription regulator β-catenin (CTNNB1, P35222) or being β-catenin-independent (often referred to as canonical vs. non-canonical WNT/FZD signalling, respectively). WNT stimulation of FZDs can, in cooperation with the low density lipoprotein receptors LRP5 (O75197) and LRP6 (O75581), lead to the inhibition of a constitutively active destruction complex, which results in the accumulation of β-catenin and subsequently its translocation to the nucleus. β-catenin, in turn, modifies gene transcription by interacting with TCF/LEF transcription factors. WNT/β-catenin-dependent signalling can also be activated by FZD subtype-specific WNT surrogates [34]. 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 heterotrimeric G proteins [13,36,44], the elevation of intracellular calcium [47], activation of cGMP-specific PDE6 [1] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [18]. Novel resonance energy transfer-based tools have allowed the study of the GPCR-like nature of FZDs in greater detail. Upon ligand stimulation, FZDs undergo conformational changes and signal via heterotrimeric G proteins [27,30,42,60-61]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling towards planar-cell-polarity-like pathways. Importantly, FZDs exist in at least two distinct conformational states that regulate pathway selection [61]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [9], as well as for β-catenin-dependent [4] and -independent [5,25] signalling. The pattern of cell signalling is complicated by the presence of additional ligands, which can enhance or inhibit FZD signalling (secreted Frizzled-related proteins (sFRP), Wnt-inhibitory factor (WIF1, Q9Y5W5) (WIF), sclerostin (SOST, Q9BQB4) or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

Receptors

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Targets of relevance to immunopharmacology are highlighted in blue

FZD1 C Show summary » More detailed page go icon to follow link

FZD2 C Show summary » More detailed page go icon to follow link

FZD3 C Show summary » More detailed page go icon to follow link

FZD4 C Show summary » More detailed page go icon to follow link

FZD5 C Show summary » More detailed page go icon to follow link

FZD6 C Show summary » More detailed page go icon to follow link

FZD7 C Show summary » More detailed page go icon to follow link

FZD8 C Show summary » More detailed page go icon to follow link

FZD9 C Show summary » More detailed page go icon to follow link

FZD10 C Show summary » More detailed page go icon to follow link

SMO C Show summary » More detailed page go icon to follow link

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Further reading

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References

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NC-IUPHAR subcommittee and family contributors

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How to cite this family page

Database page citation (select format):

Concise Guide to PHARMACOLOGY citation:

Alexander SP, Christopoulos A, Davenport AP, Kelly E, Mathie A, Peters JA, Veale EL et al. (2021) THE CONCISE GUIDE TO PHARMACOLOGY 2021/22: G protein-coupled receptors. Br J Pharmacol. 176 Suppl 1:S27-S156.