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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).

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Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [12]), are GPCRs originally identified in Drosophila [4], which are highly conserved across species. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it mediates effects in the Hedgehog signaling pathway [12]. 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. 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 [6], the elevation of intracellular calcium [13], activation of cGMP-specific PDE6 [1] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [7]. Furthermore, the phosphoprotein Dishevelled constitutes a key player in WNT/FZD signalling. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [5], as well as for 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 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.


Targets of relevance to immunopharmacology are highlighted in blue

FZD1 C Show summary » More detailed page

FZD2 C Show summary » More detailed page

FZD3 C Show summary » More detailed page

FZD4 C Show summary » More detailed page

FZD5 C Show summary » More detailed page

FZD6 C Show summary » More detailed page

FZD7 C Show summary » More detailed page

FZD8 C Show summary » More detailed page

FZD9 C Show summary » More detailed page

FZD10 C Show summary » More detailed page

SMO C Show summary » More detailed page


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Further reading

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NC-IUPHAR subcommittee and family contributors

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How to cite this family page

Database page citation:

Gunnar Schulte, Jacomijn Dijksterhuis, Julian Petersen, Elisa Arthofer, Belma Hot, Katerina Strakova, Shane Wright, Jana Valnohova, Matthias Lauth. Class Frizzled GPCRs. Accessed on 10/12/2018. IUPHAR/BPS Guide to PHARMACOLOGY,

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Christopoulos A, Davenport AP, Kelly E, Marrion NV, Peters JA, Faccenda E, Harding SD, Pawson AJ, Sharman JL, Southan C, Davies JA; CGTP Collaborators. (2017) The Concise Guide to PHARMACOLOGY 2017/18: G protein-coupled receptors. Br J Pharmacol. 174 Suppl 1: S17-S129.