Alternative titles; symbols
HGNC Approved Gene Symbol: FZD7
Cytogenetic location: 2q33.1 Genomic coordinates (GRCh38): 2:202,033,855-202,038,441 (from NCBI)
The APC tumor suppressor gene (611731), which is frequently mutated in human polyps and colon carcinomas, appears to interact with beta-catenin (116806), leading to beta-catenin degradation; mutant APC proteins found in colon carcinomas are defective in this activity and result in beta-catenin stabilization. The function of APC is inhibited by signaling pathways initiated through the secreted Wnt oncoprotein (see 164975). Members of the 'frizzled' (Fz) family of 7-transmembrane proteins act as receptors for Wnt proteins. To examine a potential role of Fz in the development and progression of human esophageal carcinoma, Tanaka et al. (1998) used a strategy based on differential display of RT-PCR products to isolate several Fz genes that are expressed in esophageal carcinoma tissue. They determined that 1 gene, designated FzE3, was specifically expressed in esophageal carcinoma tissue compared with the adjacent normal mucosa. RT-PCR analysis revealed that FzE3 expression was generally correlated with the development of poorly differentiated tumors with high metastatic potential. The predicted 574-amino acid FzE3 protein contains an N-terminal signal sequence, 10 cysteine residues typical of the cysteine-rich extracellular domain of Fz family members, 7 putative transmembrane domains, and an intracellular C-terminal tail with a PDZ domain-binding motif. FzE3 shares 78% protein sequence identity with FZD2 (600667). Based on functional studies in esophageal carcinoma cells, Tanaka et al. (1998) suggested that FzE3 gene expression may downregulate APC function and enhance beta-catenin-mediated signals in poorly differentiated human esophageal carcinomas.
Sagara et al. (1998) isolated FZD7 cDNAs from a fetal lung library. They stated that the FZD7 sequence had 20 nucleotide differences compared to that reported for FzE3 by Tanaka et al. (1998), resulting in 9 predicted amino acid substitutions. Sagara et al. (1998) noted that the substituted amino acids are conserved between FZD7 and mouse Mfz7. They suggested that the sequence differences between FZD7 and FzE3 resulted from misincorporations during the PCR-based cloning of FzE3. Northern blot analysis revealed that FZD7 is expressed as 5- and 4-kb mRNAs in several human tissues, with the highest expression in adult skeletal muscle and fetal kidney.
The frizzled-dependent signaling cascade comprises several branches whose differential activation depends on specific Wnt ligands, frizzled receptor isoforms, and the cellular context. In Xenopus embryos, the canonical beta-catenin (116806) pathway contributes to the establishment of the dorsal-ventral axis. A different branch, referred to as the planar cell polarity pathway, is essential for cell polarization during elongation of the axial mesoderm by convergent extension. Winklbauer et al. (2001) demonstrated that a third branch of the cascade is independent of dishevelled (see 601365) function and involves signaling through trimeric G proteins and protein kinase C (PKC, see 176960). During gastrulation, frizzled-7-dependent PKC signaling controls cell-sorting behavior in the mesoderm. Loss of zygotic frizzled-7 function results in the inability of involuted anterior mesoderm to separate from the ectoderm, which leads to severe gastrulation defects. Winklbauer et al. (2001) concluded that their results provide a developmentally relevant in vivo function for the frizzled/PKC pathway in vertebrates.
Using CRISPR-Cas9-mediated genomewide screens, Tao et al. (2016) identified members of the FZD family as receptors for Clostridium difficile toxin B (TcdB). TcdB bound to the cys-rich domains (CRD) of FZD proteins, with highest affinity for FZD1 (603408), FZD2, and FZD7. TcdB competed with Wnt for binding to FZDs, and binding of TcdB blocked Wnt signaling. HeLa cells lacking FZD1, FZD2, and FZD7 were highly resistant to TcdB. Recombinant FZD2-CRD prevented TcdB binding to colonic epithelium organoids and to colonic epithelium of mice. Colonic epithelium of mice lacking Fzd7 was less susceptible to TcdB-induced tissue damage than that of wildtype mice. Tao et al. (2016) concluded that FZDs are physiologically relevant receptors for TcdB in colonic epithelium.
By fluorescence in situ hybridization, Sagara et al. (1998) mapped the FZD7 gene to 2q33.
Sagara, N., Toda, G., Hirai, M., Terada, M., Katoh, M. Molecular cloning, differential expression, and chromosomal localization of human frizzled-1, frizzled-2, and frizzled-7. Biochem. Biophys. Res. Commun. 252: 117-122, 1998. [PubMed: 9813155] [Full Text: https://doi.org/10.1006/bbrc.1998.9607]
Tanaka, S., Akiyoshi, T., Mori, M., Wands, J. R., Sugimachi, K. A novel frizzled gene identified in human esophageal carcinoma mediates APC/beta-catenin signals. Proc. Nat. Acad. Sci. 95: 10164-10169, 1998. [PubMed: 9707618] [Full Text: https://doi.org/10.1073/pnas.95.17.10164]
Tao, L., Zhang, J., Meraner, P., Tovaglieri, A., Wu, X., Gerhard, R., Zhang, X., Stallcup, W. B., Miao, J., He, X., Hurdle, J. G., Breault, D. T., Brass, A. L., Dong, M. Frizzled proteins are colonic epithelial receptors for C. difficile toxin B. Nature 538: 350-355, 2016. [PubMed: 27680706] [Full Text: https://doi.org/10.1038/nature19799]
Winklbauer, R., Medina, A., Swain, R. K., Steinbeisser, H. Frizzled-7 signalling controls tissue separation during Xenopus gastrulation. Nature 413: 856-860, 2001. [PubMed: 11677610] [Full Text: https://doi.org/10.1038/35101621]