Disease relevance of FZD1

• Expression profiles of 10 members of Frizzled gene family in human gastric cancer [1].
• Redundant expression of Wnt ligands, Frizzled receptors, co-receptors and Lef/TCF transcription factors was maintained in breast cancer cell lines with some exceptions [2].
• A novel member of the human frizzled (Fz) gene family was cloned and found to be specifically expressed in 3 of 13 well differentiated (23%), 13 of 20 moderately differentiated (62%), and 12 of 14 poorly differentiated (86%) squamous cell esophageal carcinomas compared with the adjacent uninvolved normal mucosa [3].
• Wnt and frizzled receptors as potential targets for immunotherapy in head and neck squamous cell carcinomas [4].
• APF is therefore a frizzled-related peptide growth inhibitor shown to contain exclusively a transmembrane segment of a frizzled protein and is a potential biomarker for interstitial cystitis [5].

High impact information on FZD1

• Here we report that in human cells and during Xenopus embryogenesis, Wnt/Fz signaling activates the small GTPase Rho, a key regulator of cytoskeleton architecture [6].
• Our study illustrates a molecular pathway from Wnt/Fz signaling to Rho activation in cell polarity signal transduction [6].
• Wnt/Frizzled activation of Rho regulates vertebrate gastrulation and requires a novel Formin homology protein Daam1 [6].
• The identification of mutations in three distinct domains (containing Frizzled-like, kringle and tyrosine kinase motifs) indicates that these are all essential for ROR2 function [7].
• Insights into Wnt binding and signalling from the structures of two Frizzled cysteine-rich domains [8].

Biological context of FZD1

• The FZD1 and FZD7 genes have been mapped to human chromosome 7q21 and 2q33, respectively [9].
• Frizzled (FZD) genes encode seven-transmembrane type WNT receptors, which are implicated in carcinogenesis and embryogenesis [1].
• Immunoglobulin-like domain, Frizzled domain, Kringle domain within the extracellular region, tyrosine kinase domain, Ror homology C-terminal (RORHC) domain and juxta-C-terminal LLGD motif within the cytoplasmic region were conserved among vertebrate ROR1 and ROR2 orthologs [10].
• We have cloned and characterized 13 out of 19 human WNT genes, and also 9 out of 10 human Frizzled (FZD) genes encoding seven-transmembrane-type WNT receptors, which are potent targets for pharmacogenomics in the post-genomic era, especially in the field of regenerative medicine and clinical oncology [11].
• In this study, we quantified the gene expression profiles of the Wnt family, and their cognate frizzled (Fzd) receptors in primary CLL cells, and determined the role of Wnt signaling in promoting CLL cell survival [12].

Anatomical context of FZD1

• The frizzled (fz) locus in Drosophila is required for the transmission of polarity signals across the plasma membrane in epidermal cells, as well as to their neighboring cells in the developing wing [13].
• Relatively large amounts of FZD 1 mRNA, 4.5 kb in size, were detected in adult heart, placenta, lung, kidney, pancreas, prostate, and ovary and in fetal lung and kidney [9].
• In search of alternative mechanisms, we performed comprehensive expression analysis of Wnt signaling molecules, including 19 Wnt ligands, ten Frizzled receptors, two co-receptors and four Lef/TCF transcription factors in immortalized normal human mammary epithelial cells (HMEC) and six breast cancer cell lines [2].
• These data support the hypothesis that oligomerization of mutant and wild-type Fz proteins occurs in the endoplasmic reticulum and may explain the genetic dominance of this FEVR allele [14].
• However, it is not known whether other Wnts or which Frizzled (Fz) receptors are expressed in the developing midbrain [15].

Associations of FZD1 with chemical compounds

• Frizzled (FZD) receptors have a conserved N-terminal extracellular cysteine-rich domain that interacts with Wnts and co-expression of the receptor ectodomain can antagonize FZD-mediated signalling [16].
• Mutation of C-terminal serines including serine 576 significantly enhances Frizzled-3-mediated induction of neural crest markers, suggesting that C-terminal phosphorylation plays a role in down-regulating Frizzled signaling [17].
• These observations are discussed in the context of Frizzled signaling and the structure and function of other cystine knot proteins [18].
• Our results show, with high bootstrap support, five main families, named glutamate, rhodopsin, adhesion, frizzled/taste2, and secretin, forming the GRAFS classification system [19].
• The superfamily of G-protein-coupled receptors (GPCRs) could be subclassified into 7 families (A, B, large N-terminal family B-7 transmembrane helix, C, Frizzled/Smoothened, taste 2, and vomeronasal 1 receptors) among mammalian species [20].

Physical interactions of FZD1

• WNT signals, transduced through Frizzled (FZD) receptors with extracellular WNT-binding domain and cytoplasmic Dishevelled-binding domain, are implicated in carcinogenesis and embryogenesis [21].
• Canonical Wnt/Fz signaling stabilizes beta-catenin by inactivating GSK3beta, leading to the translocation of beta-catenin to the nucleus and the activation of Wnt target genes [22].
• Secreted Frizzled-related protein 1 (SFRP1) encodes a member of a protein family that contains a cysteine-rich domain similar to the WNT-binding site of Frizzled receptors and regulates the WNT pathway [23].

Regulatory relationships of FZD1

• Suppression of specific G-protein subunits suppress the ability of chimeric as well as authentic Frizzled-1 and Frizzled-2 to signal to their canonical pathways upon activation [24].
• This signaling function of beta-Catenin is activated by extracellular Wnt factors that bind to Frizzled receptors and induce inhibition of beta-Catenin degradation [25].

Other interactions of FZD1

• Here we report the identification of a human homologue for the fz gene (FZD2) [13].
• The expression of both canonical Wnt ligands and most Frizzled receptors in breast cancer cell lines suggests that canonical Wnt/beta-catenin signaling is activated in these cell lines by an autocrine/paracrine mechanism [2].
• HMEC expressed all Frizzled receptors except FZD9 and FZD10 [2].
• In 293T cells, coexpression of several Wnt-Fz fusion proteins with LRP6, but not LRP5, significantly activated a Wnt-responsive promoter, Optimized TOPFlash [26].
• Thus, this study implies that the ability to interact with Fz receptors is shared by several members of the LDLR family [27].

Analytical, diagnostic and therapeutic context of FZD1

• Molecular cloning, differential expression, and chromosomal localization of human frizzled-1, frizzled-2, and frizzled-7 [9].
• Hence, the Wnt and Fz receptors may be possible targets for immunotherapy therapy of this common cancer [4].
• We have also studied the expression of frizzled receptors 1 and 2 by immunohistochemistry in these tissues [28].
• Investigation of genetic association between human Frizzled homolog 3 gene (FZD3) and schizophrenia: results in a Korean population and evidence from meta-analysis [29].
• RT-PCR performed on purified human islets revealed that Wnt 2b, 3, 4, 5a, 7b, 10a, and 14 and Frz 4, 5, and 6 were the most highly expressed [30].

References