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.

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 coupling to G proteins is incomplete (see [6]). There is also a scarcity of information on basic pharmacological characteristics of FZDs, such as binding constants, ligand specificity or concentration-response relationships [8].

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) , 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-1 (RSPO1, Q2MKA7), R-spondin-2 (RSPO2, Q6UXX9) , R-spondin-3 (RSPO3, Q9BXY4), 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 [14], Box-5, UM206 [10], and XWnt8 (P28026) also known as mini-Wnt8.

* Key recommended reading is highlighted with an asterisk

* Angers S, Moon RT. (2009) Proximal events in Wnt signal transduction. Nat. Rev. Mol. Cell Biol., 10 (7): 468-77. [PMID:19536106]

Dijksterhuis JP, Petersen J, Schulte G. (2013) WNT/Frizzled signaling: receptor-ligand selectivity with focus on FZD-G protein signaling and its physiological relevance. Br J Pharmacol, . [PMID:24032637]

King TD, Suto MJ, Li Y. (2012) The Wnt/β-catenin signaling pathway: a potential therapeutic target in the treatment of triple negative breast cancer. J. Cell. Biochem., 113 (1): 13-8. [PMID:21898546]

King TD, Zhang W, Suto MJ, Li Y. (2012) Frizzled7 as an emerging target for cancer therapy. Cell. Signal., 24 (4): 846-51. [PMID:22182510]

Koval A, Purvanov V, Egger-Adam D, Katanaev VL. (2011) Yellow submarine of the Wnt/Frizzled signaling: submerging from the G protein harbor to the targets. Biochem. Pharmacol., 82 (10): 1311-9. [PMID:21689640]

Schuijers J, Clevers H. (2012) Adult mammalian stem cells: the role of Wnt, Lgr5 and R-spondins. EMBO J., 31 (12): 2685-96. [PMID:22617424]

Schulte G. (2010) International Union of Basic and Clinical Pharmacology. LXXX. The class Frizzled receptors. Pharmacol. Rev., 62 (4): 632-67. [PMID:21079039]

* Schulte G. (2015) Frizzleds and WNT/β-catenin signaling--The black box of ligand-receptor selectivity, complex stoichiometry and activation kinetics. Eur. J. Pharmacol., 763 (Pt B): 191-5. [PMID:26003275]

Schulte G, Schambony A, Bryja V. (2010) beta-Arrestins - scaffolds and signalling elements essential for WNT/Frizzled signalling pathways?. Br. J. Pharmacol., 159 (5): 1051-8. [PMID:19888962]

* van Amerongen R. (2012) Alternative Wnt pathways and receptors. Cold Spring Harb Perspect Biol, 4 (10). [PMID:22935904]

* Wang Y, Chang H, Rattner A, Nathans J. (2016) Frizzled Receptors in Development and Disease. Curr. Top. Dev. Biol., 117: 113-39. [PMID:26969975]

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Subcommittee members: Gunnar Schulte (Chairperson) 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

Other contributors: Jacomijn Dijksterhuis Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Julian Petersen Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Elisa Arthofer Karolinska Institutet Dept. Physiology & Pharmacology Sec. Receptor Biology & Signaling Nanna Svartz väg 2 Stockholm S-17177 Sweden Belma Hot 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 Shane Wright 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