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Frzb, a Secreted Protein Expressed in the Spemann Organizer, Binds and Inhibits Wnt-8
Open accessAbstract
We isolated a Xenopus homolog of Frzb, a newly described protein containing an amino-terminal Frizzled motif. It dorsalized Xenopus embryos and was expressed in the Spemann organizer during early gastrulation. Unlike Frizzled proteins, endogenous Frzb was soluble. Frzb was secretable and could act across cell boundaries. In several functional assays, Frzb antagonized Xwnt-8, a proposed ventralizing factor with an expression pattern complementary to that of Frzb. Furthermore, Frzb blocked induction of MyoD, an action reported recently for a dominant-negative Xwnt-8. Frzb coimmunoprecipitated with Wnt proteins, providing direct biochemical evidence for Frzb-Wnt interactions. These observations implicate Frzb in axial patterning and support the concept that Frzb binds and inactivates Xwnt-8 during gastrulation, preventing inappropriate ventral signaling in developing dorsal tissues.
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“In the extra-cellular matrix, a number of secreted proteins that bind to Wnts and prevent their interaction with either Fz or LRP5/6 to antagonize Wnt signaling have been identified. These include Dickkopf (Dkk) proteins,16 Wnt-inhibitor protein (WIF),17 soluble Frizzled-related proteins (SFRP),18 Cerebrus,19 Frzb20 and the context dependent Wnt inhibitor Wise.21”
From Wnt signal transduction pathways (2008) · cites this paper as [20]
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“Among those factors are Frzb, bearing similarity to a putative Wnt binding domain of the Frizzled receptors (Leyns et al., 1997; Moon et al., 1997; Wang et al., 1997); Dickkopf1 (Glinka et al.”
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“…are secreted which function by blocking receptor access (Semenov et al., 2001; Mao et al., 2001; Semenov et al., 2005), sequestering Wnt ligands (Wang et al., 1997; Leyns et al., 1997; Malinauskas et al., 2011) or degrading Wnt (Zhang et al., 2012; Kakugawa et al., 2015; Zhang et al., 2015).”
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“signaling by binding directly to Wnt proteins and preventing their interactions with Frizzled receptors[26,27].”
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“Secreted Frizzled Related Proteins (Sfrps) were initially and independently identified as soluble factors implicated in early embryonic development (Leyns et al. 1997; Wang et al. 1997) and as modulators of apoptotic”
BackgroundDickkopf1 and the Spemann-Mangold head organizer
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“Similar to cerberus, the Wnt antagonist frzb is expressed in the Xenopus head organizer and is capable of inducing heads in conjunction with BMP inhibitors (Leyns et al., 1997; Wang et al., 1997; Glinka et al., 1998).”
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“…al., 1996; De Robertis and Kuroda, 2004; Glinka et al., 1998; Leyns et al., 1997; Piccolo et al., 1999; Piccolo et al., 1999; Shibata et al., 2000; Wang et al., 1997) start to be expressed in the organiser, and concomitantly, Wnt8 starts to be downregulated in this territory as a consequence of…”
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Wnt pathway antagonists and angiogenesis
Zhang, B., & Ma, J. (2010) · Protein & Cell · doi:10.1007/s13238-010-0112-0 · Cited by 46
“In the study of Xenopus embryos development, sFRP3/Frzb was reported to interact with Xwnt8 and block the Xwnt-8 signaling (Leyns et al., 1997; Wang et al., 1997a).”
BackgroundEkström, E. J., Sherwood, V., & Andersson, T. (2011) · PLoS ONE · doi:10.1371/journal.pone.0018674 · Cited by 46
“accordance with previous findings in other systems [38,39,40].”
ResultSFRP1 is required for the proper establishment of the eye field in the medaka fish
Esteve, P., López-Rı́os, J., & Bovolenta, P. (2004) · Mechanisms of Development · doi:10.1016/j.mod.2004.03.003 · Cited by 46
“In Xenopus, over-expression of different SFRP family members, including FrzB, FrzA, Sizzled and Sizzled2, leads to variable degrees of embryo dorso-anteriorisation, interpreted as an acquisition of dorsal fates at the expense of the ventro-lateral domains, due to their antagonism with Wnt8 marginal activity (Leyns et…”
InfluentialLim, Y.-S., Mallapur, S., Kao, G., Ren, X., & Wadsworth, W. G. (1999) · Journal of Neuroscience · doi:10.1523/jneurosci.19-16-07048.1999 · Cited by 46
“Domains VI and V are related to the N terminus of laminin subunits, whereas domain C is shared among netrins and is related to the C terminus of Frzb, an antagonist of the Wnt receptor (Leyns et al., 1997; Wang et al., 1997).”
BackgroundEvidence for a frizzled-mediated wnt pathway required for zebrafish dorsal mesoderm formation
Nasevicius, A., Hyatt, T. M., Kim, H., Guttman, J., Walsh, E., Sumanas, S., Wang, Y., & Ekker, S. C. (1998) · Development · doi:10.1242/dev.125.21.4283 · Cited by 46
Ginsburg, G. T., & Kimmel, A. R. (1997) · Genes & Development · doi:10.1101/gad.11.16.2112 · Cited by 46
“Wnt concentration, in turn, is sensitive to the secreted, Fz-related proteins Frizzled in bone (Frzb) and Frizzled-related protein (FRP) (Leyns et al. 1997; Wang et al. 1997; J. Rubin, X.”
BackgroundSpecificity of WNT-receptor interactions
Hsieh, J.-C. (2004) · Frontiers in bioscience · doi:10.2741/1321 · Cited by 46
SFRP1 modulates retina cell differentiation through aβ-catenin-independent mechanism
Esteve, P., Trousse, F., Rodríguez, J., & Bovolenta, P. (2003) · Journal of Cell Science · doi:10.1242/jcs.00452 · Cited by 45
“…widespread expression, complementary in several locations to those of Wnts, have suggested that SFRPs could act as competitive antagonists of WNT-mediated β-catenin signalling, binding and preventing Wnt interaction with the Fz receptors (Leyns et al., 1997; Wang et al., 1997; Xu et al., 1998).”
BackgroundFormation and maintenance of the organizer among the vertebrates
Joubin, K., & Stern, C. D. (2001) · The International Journal of Developmental Biology · doi:10.1387/ijdb.11291844 · Cited by 45
“Additionally, a family of secreted Wnt inhibitors, called the Fzb’s, has been characterized (Leyns et al., 1997; Salic et al., 1997; Wang et al., 1997a; 1997b).”
BackgroundSerum Dickkopf-1 as a Biomarker for the Diagnosis of Hepatocellular Carcinoma
Kim, S. U., Park, J. H., Kim, H.-S., Lee, J. M., Lee, H. G., Kim, H., Choi, S. H., Baek, S., Kim, B. K., Park, J. Y., et al. (2015) · Yonsei Medical Journal · doi:10.3349/ymj.2015.56.5.1296 · Cited by 44
3 Molecular Regulation of Pronephric Development
Carroll, T. J., Wallingford, J. B., Seufert, D. W., & Vize, P. D. (1998) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(08)60467-6 · Cited by 44
RGS proteins inhibit Xwnt-8 signaling in Xenopus embryonic development
Wu, C., Zeng, Q., Blumer, K., & Muslin, A. J. (2000) · Development · doi:10.1242/dev.127.13.2773 · Cited by 44
Lories, R. J. U., Boonen, S., Peeters, J., de Vlam, K., & Luyten, F. P. (2005) · Lara D. Veeken · doi:10.1093/rheumatology/kei148 · Cited by 44
“The induction of autoantibodies in the treatment of ankylosing spondylitis with infliximab has also been described, but to our knowledge it has never been associated previously with induction of a lupus-like syndrome [4, 5].”
BackgroundSelf-citationHoltz, A. M., Griffiths, S. C., Davis, S. J., Bishop, B., Siebold, C., & Allen, B. L. (2015) · The Journal of Cell Biology · doi:10.1083/jcb.201411024 · Cited by 43
The APC tumor suppressor protein in development and cancer
Moon, R. T., & Miller, J. R. (1997) · Trends in Genetics · doi:10.1016/s0168-9525(97)01196-7 · Cited by 43
Suppression of GATA factor activity causes axis duplication in Xenopus
Sykes, T. G., Rodaway, A., Walmsley, M. E., & Patient, R. K. (1998) · Development · doi:10.1242/dev.125.23.4595 · Cited by 43
Completion of the epithelial to mesenchymal transition in zebrafish mesoderm requires Spadetail
Row, R. H., Maître, J., Martin, B. L., Stockinger, P., Heisenberg, C., & Kimelman, D. (2011) · Developmental Biology · doi:10.1016/j.ydbio.2011.03.025 · Cited by 42
“MBT acts to promote ventral/lateral mesoderm and to repress axial fates (Glinka et al., 1998; Hashimoto et al., 2000; Leyns et al., 1997; Ramel and Lekven, 2004; Salic et al., 1997; Wang et al., 1997).”
Nishimoto, K., Rigsby, C. S., Wang, T., Mukai, K., Gómez-Sánchez, C. E., Rainey, W. E., & Seki, T. (2012) · Endocrinology · doi:10.1210/en.2011-1915 · Cited by 42
“The gene is initially identified through its sequence similarity with the Drosophila gene Frizzled (45) and shown to inhibit the Wnt signaling (46, 47).”
BackgroundMao, C. D., Tahlil, O., Pueyo, M. E., Steg, P. G., & Soubrier, F. (2000) · Arteriosclerosis Thrombosis and Vascular Biology · doi:10.1161/01.atv.20.1.43 · Cited by 42
Joint homeostasis, restoration, and remodeling in osteoarthritis
Lories, R. J. U. (2008) · Best Practice & Research Clinical Rheumatology · doi:10.1016/j.berh.2007.12.001 · Cited by 41
Regulation of Secreted Frizzled-related Protein-1 by Heparin
Zhong, X., Desilva, T., Lin, L., Bodine, P. V. N., Bhat, R. A., Presman, E., Pocas, J. R., Stahl, M., & Kriz, R. (2007) · Journal of Biological Chemistry · doi:10.1074/jbc.m609096200 · Cited by 43
Metadata
- Authors
- Wang, S., Krinks, M., Lin, K., Luyten, F. P., & Moos, M.
- Affiliations
- United States Food and Drug Administration (US)
- Center for Biologics Evaluation and Research (US)
- National Institutes of Health (US)
- Corresponding author
- Moos, Malcolm
- Venue
- Cell
- Publisher
- Elsevier BV
- Published
- 1997-03
- Volume
- 88
- Issue
- 6
- Pages
- 757-766
- ISSN
- 0092-8674 (ISSN-L)
- OpenAlex
- W1988350691
- Cited by
- 518
- References
- 70
- Citations by year
- 2026: 3 · 2025: 11 · 2024: 8 · 2023: 9 · 2022: 11 · 2021: 6 · 2020: 12 · 2019: 3 · 2018: 13 · 2017: 17 · 2016: 6 · 2015: 12 · 2014: 15 · 2013: 9 · 2012: 14
- FWCI
- 17.08
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Cell (publishedVersion)
- PubMed (publishedVersion)
- Funders
- George Washington University
- National Institutes of Health
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Health Sciences › Medicine › Oncology › Renal and related cancers
- Keywords
- FRZB, Spemann organizer, dorsalization, ventralization, gastrulation, axial patterning, MyoD, Wnt signaling inhibition, secreted proteins, Xenopus embryo
- MeSH terms
- Frizzled-Related Proteins, Animals, Biological Transport, Cell Communication, Dogs, Embryonic Induction, Female, Glycoproteins, Male, Mesoderm, Microsomes, Protein Binding, Proteins, Rabbits, RNA, Messenger, Solubility, Transcription, Genetic, Xenopus, Zygote, MyoD Protein, Gene Expression Regulation, Developmental, COS Cells, Zebrafish Proteins, Intracellular Signaling Peptides and Proteins, Wnt Proteins
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