Frizzled Class GPCRs

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 [11]), are GPCRs originally identified in Drosophila [4], which are highly conserved across species. FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins 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 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 pertussis toxin-sensitive heterotrimeric G proteins [9], the elevation of intracellular calcium [12], 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 Disheveled constitutes a key player in WNT/FZD signalling. 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 [3,10] 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 (SOST, Q9BQB4)) or Dickkopf (DKK)), as well as modulatory (co)-receptors with positive Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

Receptors

FZD1 Show summary » More detailed page

FZD2 Show summary » More detailed page

FZD3 Show summary » More detailed page

FZD4 Show summary » More detailed page

FZD5 Show summary » More detailed page

FZD6 Show summary » More detailed page

FZD7 Show summary » More detailed page

FZD8 Show summary » More detailed page

FZD9 Show summary » More detailed page

FZD10 Show summary » More detailed page

SMO Show summary » More detailed page

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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:

Frizzled Class GPCRs. Accessed on 20/09/2014. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/FamilyDisplayForward?familyId=25.

Concise Guide to PHARMACOLOGY citation:

Alexander SPH, Benson HE, Faccenda E, Pawson AJ, Sharman JL, Spedding M, Peters JA and Harmar AJ, CGTP Collaborators. (2013) The Concise Guide to PHARMACOLOGY 2013/14: G Protein-Coupled Receptors. Br J Pharmacol. 170: 1459–1581.