1. National Institute of Child Health and Human Development, USA
2. Karolinska Institutet, Sweden
3. Philipps-Universität Marburg, Germany

Abstract

Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [175]), are GPCRs originally identified in Drosophila [19], 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 [175]. 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 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-independent signalling can also be activated by FZD subtype-specific WNT surrogates [133]. 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 [33, 178, 150], the elevation of intracellular calcium [184], activation of cGMP-specific PDE6 [2] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [56]. 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 [239, 240, 102, 174]. 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 [240]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [22], as well as for β-catenin-dependent [13] and -independent [89, 14] 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 (WIF), sclerostin or Dickkopf (DKK)), as well as modulatory (co)-receptors with Ryk, ROR1, ROR2 and Kremen, which may also function as independent signalling proteins.

Contents

GtoPdb is an expert-driven guide to pharmacological targets and the substances that act on them. GtoPdb is a reference work which is most usefully represented as an on-line database. As in any publication this work should be appropriately cited, and the papers it cites should also be recognized. This document provides a citation for the relevant parts of the database, and also provides a reference list for the research cited by those parts. For further details see [15].

Please note that the database version for the citations given in GtoPdb are to the most recent preceding version in which the family or its subfamilies and targets were substantially changed. The links below are to the current version. If you need to consult the cited version, rather than the most recent version, please contact the GtoPdb curators.

Database links

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