General

Frizzleds are seven-transmembrane-spanning receptors which have an important physiological role during embryonic development [2] and also tissue homeostasis in the adult. They are associated with a series of diseases in both animal models and man [3,10,15,18]. So far 10 mammalian FZDs (FZD_1-10) have been identified, showing the gross topology of GPCRs with an extracellular N-terminus, three extra- and three intracellular loops, seven transmembrane-spanning helices and an intracellular C-terminal domain. The large N-terminus contains the predicted orthosteric ligand binding site, the cystein-rich domain (CRD domain) of the receptor [4,11]. The C-terminus and especially a highly conserved internal PDZ domain are important for FZD signal transduction and recruitment of intracellular effectors.

The Class Frizzled family of receptors indeed presents an unconventional family of GPCRs [5-6,25-26] since primary signalling pathways activated by FZDs do not correspond with signal transduction via classical GPCRs. In general, signalling via FZDs can be divided into pathways that depend on the transcriptional regulator β-catenin and those that are independent of β-catenin, originally called canonical and non-canonical pathways (for recent reviews on FZD signalling see [2,5,8,12-13,16-17,20,30,32]).

Ligands

The cognate ligands of the FZDs are the WNTs, a family of secreted, lipoglycoproteins of 19 mammalian members [32]. The lack of pure and biologically active WNTs has hampered the development of the FZD field enormously and this is one reason for the lack of basic pharmacological information such as receptor-ligand specificity/promiscuity, binding constants, kinetics of receptor-ligand interaction and intracellular signalling. Several representatives of mammalian WNTs are now available in purified and biologically active form and some progress has been made in the characterisation of pharmacological parameters [27,31,33]. However, quantitative information regarding WNT-binding to individual full length FZD is still not available even though WNT-FZD-CRD interactions have been quantified with affinities in the nanomolar range [9]. Further, several other secreted proteins were shown to bind and activate FZDs, such as the CTGF (connective tissue growth factor), Norrin and sFRPs (soluble FZD-related proteins) [2,25].

Coreceptors

Different coreceptors were shown to bind WNTs and to modulate FZD pharmacology and signalling. These coreceptors might be factors conveying specificity to different WNT/FZD combinations. Of main importance are the LRP5/6 for β-catenin-dependent signalling and ROR1, ROR2, RYK for β-catenin-independent signalling pathways [1,7-8,30].

Smoothened

Smoothened (SMO) is a seven-transmembrane-spanning protein and presents a central part of the hedgehog signalling system [23], which is of eminent importance for proper embryogenesis and tumorigenesis [28-29]. SMO, however, is not the hormone-sensing receptor of this intricate signalling system, it was rather described as a signalling switch [14]. The secreted lipoglycoproteins [19] of the hedgehog family (sonic, Indian and desert hedgehog) bind the transmembrane protein patched (PTCH1, PTCH2), which constitutively inhibits SMO. Upon hedgehog binding to PTCH, this inhibition is released, resulting in the activation of SMO and initiation of SMO-downstream signalling. Similar to the FZD family of receptors it is suggested but not proven that SMO could be a GPCR signalling mainly through G_i/o family G proteins [22-24]. With regard to the complexity of information flow from the secreted ligand to SMO and intracellular signalling pathways [21], it becomes obvious that parameters of receptor pharmacology cannot be conceived as in the case of classical GPCRs.

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