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.

There is limited knowledge about WNT/FZD specificity and which molecular entities determine the signalling outcome of a specific WNT/FZD pair. Understanding of the FZD and SMO coupling to G proteins is incomplete, but progress have been made [2,12-13,24,33,37-38,41,45,54,60]. There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration-response relationships [23]. However, progress in understanding WNT-FZD interactions has been initiated with generation of eGFP-tagged WNT-3A and its use in BRET-based binding assays [29,51,59]. Development of pharmacological tools [28] for SMO has been faciliated by successful determination of several SMO structures [6,12,21,26,37-38,55-56,58,64-65]. The recently solved FZD₄ and FZD₅ structures in apo state, as well as the structure of FZD₇ bound to a heterotrimeric Gs protein, have provided first insights into FZD transmembrane organization [52,62-63].

Ligands associated with FZD signalling
WNTs: Wnt-1 (WNT1, P04628), Wnt-2 (WNT2, P09544) (also known as Int-1-related protein), Wnt-2b (WNT2B, Q93097) (also known as WNT-13), Wnt-3 (WNT3, P56703) , Wnt-3a (WNT3A, P56704), Wnt-4 (WNT4, P56705), Wnt-5a (WNT5A, P41221) (pEC50 7.7-8.9 [60]), Wnt-5b (WNT5B, Q9H1J7), Wnt-6 (WNT6, Q9Y6F9), Wnt-7a (WNT7A, O00755), Wnt-7b (WNT7B, P56706), Wnt-8a (WNT8A, Q9H1J5), Wnt-8b (WNT8B, Q93098), Wnt-9a (WNT9A, O14904) (also known as WNT-14), Wnt-9b (WNT9B, O14905) (also known as WNT-15 or WNT-14b), Wnt-10a (WNT10A, Q9GZT5), Wnt-10b (WNT10B, O00744) (also known as WNT-12), Wnt-11 (WNT11, O96014) and Wnt-16 (WNT16, Q9UBV4).

Extracellular proteins that interact with FZDs: norrin (NDP, Q00604), R-spondin-4 (RSPO4, Q2I0M5), sFRP-1 (SFRP1, Q8N474), sFRP-2 (SFRP2, Q96HF1), sFRP-3 (FRZB, Q92765), sFRP-4 (SFRP4, Q6FHJ7), sFRP-5 (SFRP5, Q6FHJ7).

Extracellular proteins that interact with WNTs or LRPs: Dickkopf 1 (DKK1, O94907), WIF1 (Q9Y5W5), sclerostin (SOST, Q9BQB4), kremen 1 (KREMEN1, Q96MU8) and kremen 2 (KREMEN2, Q8NCW0)

Small exogenous ligands: Foxy-5 [49], Box-5 [22], UM206 [31], and XWnt8 (P28026) also known as mini-Wnt8.

Ligands associated with SMO signalling: cholesterol, oxysterols [6,32,39].

* Key recommended reading is highlighted with an asterisk

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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 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