Receptors of the Class Frizzled (FZD, nomenclature as agreed by the NC-IUPHAR subcommittee on the Class Frizzled GPCRs [45]), are GPCRs highly conserved across species and were originally identified in Drosophila [8]. While SMO shows structural resemblance to the 10 FZDs, it is functionally separated as it is involved in Hedgehog signaling [45]. SMO exerts its effects by activating heterotrimeric G proteins or stabilization of GLI by sequestering catalytic PKA subunits [3,23,48]. While SMO itself is bound by sterols and oxysterols [11,28], FZDs are activated by WNTs, which are cysteine-rich lipoglycoproteins with fundamental functions in ontogeny and tissue homeostasis. FZD signaling 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 signaling, respectively). Nevertheless, it makes pharmacologically more sense to define downstream signaling by transducer coupling to either DVL or heterotrimeric G proteins [46]. 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 [36]. 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 [14,38,47], the elevation of intracellular calcium [50], activation of cGMP-specific PDE6 [1] and elevation of cAMP as well as RAC-1, JNK, Rho and Rho kinase signalling [22]. 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 [4,20,31,33,44,61-62]. Furthermore, the phosphoprotein Dishevelled constitutes a key transducer in WNT/FZD signaling towards planar-cell-polarity-like pathways. Importantly, FZDs adopt distinct conformational landscapes that regulate pathway selection [18,62]. As with other GPCRs, members of the Frizzled family are functionally dependent on the arrestin scaffolding protein for internalization [10], as well as for β-catenin-dependent [5] and -independent [6,27] 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 PTK7, which may also function as independent signaling proteins. An important FZD₄-selective non-WNT agonist is the norrin (NDP, Q00604) cysteine knot protein, which is a key player in FZD₄-mediated vascularization for example in the retina and which is functionally related to familial exudative vitreoretinopathy (FEVR).

There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Recent insights into protein dynamics, activation mechanisms, conserved microswitches, and co-receptor involvement of FZDs have advanced our understanding in being able to target this enigmatic class of receptors as drug targets [4,18,20,29,57]. Findings with recent reported small molecules were not reproducible, including FzM1.8 and carbamazepine, highlighting the limitations in the assays available [30,53]. Understanding of FZD and SMO coupling to heterotrimeric G proteins is incomplete, but progress has been made [2,13-14,26,35,39-40,43,48,56,61]. Development of pharmacological tools [32] for SMO has been faciliated by successful determination of several SMO structures [7,13,25,32,39-40,58-59,65-66]. The increase in FZD structures including FZD_1,3,6,7 in apo and active states and a recent FZD₄ complex with DEP have provided insights into FZD transmembrane organization and intracellular transducer coupling [29,41,54,63-64,67]. FZD₇ has emerged as a particularly interesting WNT receptor by primarily modulating carcinogenesis, metastasis, and chemoresistance [34]. Recent pharmacological and structural studies highlight FZD₇ in the context of intenstinal cancer and its interaction with the virulence factor, TcdB [19,29].

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Subcommittee members: Gunnar Schulte (Chairperson) Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Biomedicum Quarter 6D Solnavägen 9 17165 Solna Sweden Paweł Kozielewicz Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Biomedicum Quarter 6D Solnavägen 9 17165 Solna Sweden

Other contributors: Elisa Arthofer National Institute of Child Health and Human Development 35 A Convent Dr, Room 2D993 Bethesda, MD, 20892 USA Jacomijn Dijksterhuis Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Lukas Grätz Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Biomedicum Quarter 6D Solnavägen 9 17165 Solna Sweden Belma Hot Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Julia Kinsolving Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Biomedicum Quarter 6D Solnavägen 9 17165 Solna Sweden Matthias Lauth Institut für Molekularbiologie und Tumorforschung (IMT) Emil-Mannkopff-Str. 2 35033 Marburg Julian Petersen Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Katerina Strakova Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Jana Valnohova Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Shane Wright Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden