FZD5 (frizzled class receptor 5)

Alias (NCBI)	C2orf31 (Chromosome 2 open reading frame 31)
	Frizzled-5, seven transmembrane spanning receptor,
	HFZ5
	Fz-5
	DKFZP434E2135
	FzE5
HGNC (Hugo)	FZD5
HGNC Alias symb	HFZ5
	DKFZP434E2135
HGNC Previous name	C2orf31
HGNC Previous name	frizzled (Drosophila) homolog 5
	chromosome 2 open reading frame 31
	frizzled homolog 5 (Drosophila)
	frizzled 5, seven transmembrane spanning receptor
	frizzled family receptor 5
LocusID (NCBI)	7855
Atlas_Id	47614
Location	2q33.3 [link to chromosomal band 2q33.  [Link to chromosome band 2q33]
Location_base_pair	Starts at 207762601 and ends at 207769906 bp from pter ( according to hg19-Feb_2009)  [Mapping FZD5.png]
	Figure 1: A) Location of FZD5 gene on chr2. B) Schematic representation of FZD5 gene, with exons 1 and 2. C) Protein structure and the subdivision into various domains.

Note	The FZD5 gene (6978 bp) contains a total of 2 exons and the FZD5 transcript is 6708 bp.
	Figure 2: Schematic representation of FZD5 gene.
Description	Genomic size: 6978 bp. Exons count: 2, only one of which is coding. This gene has 1 transcript (splice variant), 66 orthologues, 12 paralogues.
Transcription	1 transcript variant has been found for this gene (font. www.ensembl.org). FZD5-201 ENST00000295417.3: mRNA 6708 bp, protein 585 aa.

	Figure 3: Schematic illustration of domains of FZD5 protein.
Description	FZD5 protein, comprised of 585 aa with a mass of 64 kDa, is part of the frizzled gene family, 7-transmembrane domain proteins, which includes 10 members (FZD1 to FZD10). The FZD1-10 are bound and activated by the WNT family of lipoglycoproteins, inducing a network of signalling pathways: the WNT-FZD signalling system has a prevalent role in physiology during adulthood and dysfunction of this signalling leads to diseases, such as cancer and neurological and bone disorders. Wnt signals are transduced through at least three different pathways, including the canonical Wnt/β-catenin pathway, the Wnt/Ca2+ pathway, and the non-canonical planar cell polarity (PCP). The exclusive involvement of FZD5 in one of these three pathways is unclear, although some cases have been reported that WNT5A activate the canonical pathway in the presence of overexpressed FZD5 (He et al., 1997) and that WNT7A interacts with FZD5 to activate CTNNB1 (β-catenin)/canonical signalling (Carmon and Loose, 2008); however other evidences report that FZD5 can been associated with non-canonical Wnt signalling (Bischoff et al., 2015). The secondary structure of FZD5 protein is composed by a large domain, the FZ domain, and two motifs, the Lys-Thr-X-X-X-Trp motif, and the PDZ-binding motif. The FZ domain (from aa 28 to aa 150) is an intracellular domain of about 120 amino acids, located close to the N-terminal end, first identified in the alpha-1 chain of mouse type XVIII collagen (Rehn and Pihlajaniemi, 1995). The FZ domain, also known as CRD (cysteine rich domain) contains 10 conserved cysteines, and its crystal structure shows predominance of α -helix with disulphide bonds. Its presence is widely demonstrated to be involved in Wnt signalling (Povelones et al., 2005). The C-terminal cytoplasmic Lys-Thr-X-X-X-Trp motif (from aa 525 to aa 530) is located two amino acids after the seventh TM and frizzled receptors with point mutations into this motif lose their capacity to activate Wnt/β-catenin signalling (Umbhauer et al., 2000). The PDZ domain (from aa 583 to aa 585) is a structural domain found in the signalling proteins and it plays a role in transport, ion channel signalling and transduction system, that typically recognize the extreme C-terminal end of the target proteins (Lee and Zheng, 2010).
	Figure 4: Visualization of WNT10B-FZD5 interaction in MCF-7 adherent cells (Lazzaroni et al., 2016).
Expression	Ishikawa et al. (2001) first isolated and characterized this novel mouse frizzled gene Fzd5. Its mRNA was expressed in the yolk sac, eyes and lung bud at 9.5 days post coitum, demonstrating its essential role in development. In Xenopus embryos, after determining synergistic interactions between Wnts and frizzleds, misexpression, disruption or depletion of these components of Wnt pathway can inhibit the dorsal axis formation: these results suggest that the frizzled proteins work as receptors for Wnt ligands. To confirm that, Ishikawa et al. presents the evidence that the homozygous Fzd5 knockout mice are embryonically lethal, due to the defects they develop in the yolk sac vasculogenesis. Fzd5 is expressed in the developing retina in zebrafish, Xenopus Laevis, chick and mouse. Later, human FZD5 was mapped on chromosome 2q33.3-q34 (Saitoh et al., 2001) and one of its ligand, WNT7A, activate Wnt/β-catenin signalling pathway and cell motility/invasion in metastatic melanoma, endometrial and ovarian cancer cell lines (Carmon and Loose, 2008, Ueno et al., 2013).
Localisation	FZD5 is localized at the plasma membrane and it is also found at the Golgi apparatus membrane. (UniProt FZD5)
Function	FZD5 is part of the 7-transmembrane domain proteins, receptors for Wnt signalling proteins. When the Wnt signalling pathway is activated, FZD receptors are internalized in response to their Wnt ligands: internalization of FZD5 is induced by WNT3A, complexed with LRP6 (Yamamoto et al., 2006). A recent study (Terabayashi et al., 2009) demonstrated that FZD5 is internalized in response to WNT3A stimulation via the clathrin-dependent pathway to activate downstream signalling pathways. Terabayashi et al., found that the expression of SCYL2 (CVAK104), a coated vesicle-associated kinase of 104 kDa which is part of the endocytic process, induces intracellular accumulation of FZD5 and the latter is internalized and degraded by a lysosomal pathway, suggesting a model for regulating the turnover of specific subclass of FZD receptors. FZD5 protein is believed to be the receptor for the WNT5A ligand, in some contexts such as the induction of Tissue Factor (TF) expression for angiogenesis in monocytes (Arderiu et al., 2014), or in the pancreatic cancer context. This interaction between WNT5A and FZD5 results in activation of the Wnt/β-catenin canonical pathway, therefore FZD5 can be considered as a receptor for WNT5A (He et al., 1997). Other evidences of interaction of FZD5 with WNT5A have been provided by Ishikawa et al., investigating the presence of WNT5A and WNT10B in the yolk sac and inducing the formation of secondary axes in Xenopus. The synergy between WNT10B and FDZ5 has been proved by Lazzaroni et al., (2016), confirming an autocrine mechanism for Wnt signalling activation in a breast cellular model (MCF7). Moreover, FZD5 conjugated with LRP6 can interact and transduce a WNT7A signal for the activation of Wnt/β-catenin canonical signalling pathway and for the induction of proliferation in endometrial cancer cells (Carmon and Loose, 2008). WNT2 is also a FZD5 ligand, and WNT2 deficient embryos show placental defects, suggesting their role in vascular growth during the developmental stage (Ishikawa et al., 2001). FZD5 seems to have also an important role in the early stage of the eye development; this function may be species-dependent (Carole et al., 2008). Other findings have discovered a FZD5's role in neuronal development and polarity. Starting from the evidence that WNT3A is essential for neuronal differentiation of hNP cells, Bengoa-Vergniory et al., (2016) has performed the silencing of its receptors FZD4, FZD5, ROR1 and LRP6 and has shown a trend for reducing neuronal differentiation and gene expression. Instead, Slater et al., (2013) suggests a role for FZD5, in cell culture of hippocampal neurons of rat, in the establishment of neuronal polarity and in its morphogenesis, through the non-canonical Wnt mechanism.
Homology	The FZD5 gene is conserved in chimpanzee, dog, cow, mouse, rat, chicken, zebrafish. The characteristic domain Fz, also known as CRD domain, is conserved in all the members of the Frizzled family

	Figure 5: Overview of major types of mutations occurring in FZD5.
Germinal	Liu et al., (2016) reports an ultra-rare heterozygous frameshift mutation in FZD5 (p. Ala219Glufs*49) responsible of autosomal dominant non-syndromic coloboma. This frameshift variant is not a canonical substrate for nonsense-mediated decay, so the result is the production of a truncated protein, that lacks the transmembrane domain. The truncated protein is secreted from cells and becomes a dominant-negative FZD5 receptor, so it antagonises both canonical and non-canonical WNT signalling.
Somatic	Wang et al., (2014) has observed 2 mutations in FZD5 that led to loss of functional pathway activation. The first one (p. Y46*) is a nonsense mutation that results in a premature truncation of the protein, generating a new protein (MT1) that led to a loss of Wnt-activating function. The second one (p. V290I) is a missense mutation that produces the protein named MT2. MT2, in contrast to MT1, did not change Wnt pathway activity. Some somatic mutations have been identified and described by COSMIC (Catalogue of Somatic Mutation In Cancer) and most are listed as nonsense, missense and synonymous substitutions; nevertheless, their role in disease has not yet been clarified.

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