Frizzled receptors (FZDs) are a family of seven-span transmembrane receptors with hallmarks of G protein-coupled receptors (GPCRs) that serve as receptors for secreted Wingless-type (WNT) ligands in the WNT signaling pathway. Functionally, FZDs play crucial roles in regulating cell polarity, embryonic development, cell proliferation, formation of neural synapses, and many other processes in developing and adult organisms. The frizzled receptors (FZDs) are comprised of ten members (FZD1–FZD10). The common characteristics of these members include an N-terminal signal sequence followed by highly conserved cysteine-rich domain (CRD) in extracellular region, a seven-pass transmembrane domain and an intracellular C-terminal domain. The WNT proteins, a kind of secreted glycoproteins and ligands of FZDs, are comprised of nineteen members which can bind to the cell surface complex consisted of two elements: a member of the FZD family and the co-receptor Low density lipoprotein receptor related protein 5/6 (LRP5/6). Other heterodimeric receptor complexes comprised of an FZD and the cell surface receptors encoded by the receptor tyrosine kinase like orphan receptor 2 (ROR2) and receptor-like tyrosine kinase (RYK) genes have also been described. Subsequently, the intracellular C-terminal domain of FZDs interacts with the Dishevelled (DVL) protein to transduce the WNT signals to the downstream of the pathway. Each member of FZDs can interact with several different WNT proteins to activate either the canonical WNT/β-catenin or the non-canonical WNT/PCP (planar cell polarity) and WNT/Ca2+ signaling pathways, thereby activating multiple downstream transcription factors that are important for stem cell regulation, embryonic development, cell polarity, proliferation and differentiation, and especially tumorigenesis. To date, the selectivity between individual WNTs and FZDs remains poorly understood. Taking a panoramic view of the WNT signaling pathway, it is easy for us to draw a conclusion that FZDs serve as a core component in both canonical and non-canonical pathways. It is worth mentioning that the co-receptors also play a key role in forming a complex with FZDs for binding WNT ligands and are involved in tumorigenesis. Additionally, hetero-dimerization of FZDs and co-receptors is well-known. Nile et al. recently reported that the CRD of FZDs recognized WNT cis-unsaturated fatty acyl groups which bridged two CRD monomers and mediated FZD receptor dimerization. Earlier, Carron et al. implied that FZD receptor dimerization contributed to transduction of WNT/β-catenin signaling.
Structural Features of Frizzled Receptors
FZDs could be further divided into four subgroups according to their identity. FZD1, FZD2, and FZD7 share about 75% identity with each other, FZD4, FZD9, and FZD10 share 65% identity, FZD5 and FZD8 share 70% identity, FZD3 and FZD6 share 50% amino acid identity. The range of identities shared by receptors from different subgroups is from 20 to 40%. The length of FZDs ranges from 500 to 700 amino acids. The extracellular CRD comprises of 120 to 125 amino residues with ten conserved cysteines and is followed by a hydrophilic linker region which contains 40 to 100 amino residues. The proteins also contain seven hydrophobic domains that are predicted to form transmembrane α-helices. The length of the intracellular C-terminal domain is variable and is not very conserved compared with each family member.
In addition to the basic structural features of FZDs, the common characteristics between FZDs and other GPCRs include the following: (1) the conserved cysteines in the extracellular loops 1 and 2 that are implicated in the formation of disulfide bonds and (2) a series of charged residues at the N- and C-terminal of intracellular loop 3 that are indispensable for the coupling of receptor and G protein. However, FZDs lack some domains common to other GPCRs, such as the DRY motif at the C-terminal end of the third transmembrane domain.
Biological Functions and Mechanism
The biological functions of FZDs have been elucidated in various cancers and in normal development. A lot of functions that promote cancer are mediated by FZDs including cancer cell proliferation, migration, invasion, angiogenesis, stemness, and chemoresistance after cancer recurrence. Notably, FZDs do not work through a single, well-known WNT signaling pathway but are intertwined with other signaling cascades.
1. Zeng CM; et al. Frizzled receptors as potential therapeutic targets in human cancers. International Journal of Molecular Sciences, 2018,19(5):1543.