Alternative titles; symbols
HGNC Approved Gene Symbol: FZD1
Cytogenetic location: 7q21.13 Genomic coordinates (GRCh38): 7:91,264,433-91,271,326 (from NCBI)
Frizzled proteins, such as FZD1, are 7-transmembrane domain-containing receptors whose extracellular cysteine-rich domains (CRDs) bind to Wnt proteins (see 164975). Wnts are secreted cell signaling proteins involved in development and homeostasis (summary by Zilberberg et al., 2004).
Sagara et al. (1998) cloned fetal lung cDNAs encoding FZD1, FZD2 (600667), and FZD7 (603410). The predicted 647-amino acid FZD1 protein contains a signal peptide, a CRD in the N-terminal extracellular region, 7 transmembrane domains, and a C-terminal PDZ domain-binding motif. FZD1 shares 77% and 74% protein sequence identity with FZD2 and FZD7, respectively. Northern blot analysis revealed that FZD1 is expressed as a 4.5-kb mRNA in various tissues.
By fluorescence in situ hybridization, Sagara et al. (1998) mapped the FZD1 gene to 7q21.
Liu et al. (2001) constructed a chimeric receptor with the ligand-binding and transmembrane segments from the beta-2-adrenergic receptor (109690) and the cytoplasmic domains from rat frizzled-1. Stimulation of mouse F9 clones expressing the chimera with the beta-adrenergic agonist isoproterenol stimulated stabilization of beta-catenin (116806), activation of a beta-catenin-sensitive promoter, and formation of primitive endoderm. The response was blocked by inactivation of pertussis toxin-sensitive, heterotrimeric G proteins, and by depletion of G-alpha-q (600998) and G-alpha-o (139311). Thus, Liu et al. (2001) concluded that G proteins are elements of Wnt/frizzled-1 signaling to the beta-catenin-lymphoid-enhancer factor (LEF)-T-cell factor (Tcf) pathway.
Hematopoietic stem cells (HSCs) have the ability to renew themselves and to give rise to all lineages of the blood. Reya et al. (2003) showed that the WNT signaling pathway has an important role in this process. Overexpression of activated beta-catenin expands the pool of HSCs in long-term cultures by both phenotype and function. Furthermore, HSCs in their normal microenvironment activate a LEF1/TCF (153245) reporter, which indicates that HSCs respond to WNT signaling in vivo. To demonstrate the physiologic significance of this pathway for HSC proliferation, Reya et al. (2003) showed that the ectopic expression of axin (603816) or a frizzled ligand-binding domain, inhibitors of the WNT signaling pathway, led to inhibition of HSC growth in vitro and reduced reconstitution in vivo. Furthermore, activation of WNT signaling in HSCs induced increased expression of HOXB4 (142965) and NOTCH1 (190198), genes previously implicated in self-renewal of HSCs. Reya et al. (2003) concluded that the WNT signaling pathway is critical for normal HSC homeostasis in vitro and in vivo, and provide insight into a potential molecular hierarchy of regulation of HSC development.
Zilberberg et al. (2004) noted that members of the low density lipoprotein receptor family, including LRP5 (603506) and LRP6 (603507), interact with frizzled receptors and function as Wnt coreceptors. Using transfected HEK293 cells, they showed that LRP1 (107770), as well as a C-terminal fragment of LRP1 that mimics the full-length protein, bound the CRD of human FZ1 and inhibited FZ1-dependent Wnt signaling. LRP1 did not mediate FZ1 internalization and degradation, but sequestered FZ1 and inhibited its formation of a functional Wnt signaling complex with LRP6.
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 CRDs of FZD proteins, with highest affinity for FZD1, 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.
Liu, T., DeCostanzo, A. J., Liu, X., Wang, H., Hallagan, S., Moon, R. T., Malbon, C. C. G protein signaling from activated rat frizzled-1 to the beta-catenin-Lef-Tcf pathway. Science 292: 1718-1722, 2001. [PubMed: 11387477] [Full Text: https://doi.org/10.1126/science.1060100]
Reya, T., Duncan, A. W., Ailles, L., Domen, J., Scherer, D. C., Willert, K., Hintz, L., Nusse, R., Weissman, I. L. A role for Wnt signalling in self-renewal of haematopoietic stem cells. Nature 423: 409-414, 2003. [PubMed: 12717450] [Full Text: https://doi.org/10.1038/nature01593]
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]
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]
Zilberberg, A., Yaniv, A., Gazit, A. The low density lipoprotein receptor-1, LRP1, interacts with the human frizzled-1 (HFz1) and down-regulates the canonical Wnt signaling pathway. J. Biol. Chem. 279: 17535-17542, 2004. [PubMed: 14739301] [Full Text: https://doi.org/10.1074/jbc.M311292200]