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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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Qian, D., Jones, C., Rzadzinska, A. K., Mark, S., Zhang, X., Steel, K. P., Dai, X., & Chen, P. (2007) · Developmental Biology · doi:10.1016/j.ydbio.2007.03.011 · Cited by 422
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Wei, C. L., Miura, T., Robson, P., Lim, S. K., Xu, X., Lee, M. Y., Gupta, S. M., Stanton, L. W., Luo, Y., Schmitt, J., et al. (2005) · Stem Cells · doi:10.1634/stemcells.2004-0162 · Cited by 212
LRP5 and Wnt Signaling: A Union Made for Bone
Johnson, M. L., Harnish, K., Nusse, R., & Hul, W. V. (2004) · Journal of Bone and Mineral Research · doi:10.1359/jbmr.040816 · Cited by 211
Dabdoub, A., Donohue, M. J., Brennan, A., Wolf, V., Montcouquiol, M., Sassoon, D. A., Hseih, J.-C., Rubin, J. S., Salinas, P. C., & Kelley, M. W. (2003) · Development · doi:10.1242/dev.00448 · Cited by 211
Lee, A. Y., He, B., You, L., Dadfarmay, S., Xu, Z., Mazières, J., Mikami, I., McCormick, F. P., & Jablons, D. M. (2004) · Oncogene · doi:10.1038/sj.onc.1207881 · Cited by 209
“…(2004) 23, 6672–6676 & 2004 Nature Publishing Group All rights reserved 0950-9232/04 $30.00 www.nature.com/onc based on their ability to bind and sequester the Wnt ligands, provide an important method for modulating Wnt signaling (Hu et al., 1998; Wang et al., 1997).”
InfluentialGhiglione, C., Carraway, K. L., Amundadottir, L. T., Boswell, R. E., Perrimon, N., & Duffy, J. B. (1999) · Cell · doi:10.1016/s0092-8674(00)80594-2 · Cited by 206
The molecular nature of the zebrafish tail organizer
Agathon, A., Thisse, C., & Thisse, B. (2003) · Nature · doi:10.1038/nature01822 · Cited by 206
“or through overexpression of a Wnt-specific inhibitor, Frz”
Wnt Signalling in Mammalian Development and Cancer
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“The largest family of such proteins so far discovered are the secreted Frizzled-Related Proteins (sFRP) 1–5 [95–101].”
BackgroundMii, Y., & Taira, M. (2009) · Development · doi:10.1242/dev.032524 · Cited by 205
“, 2008)] and Crescent (Cres) are thought to negatively regulate Wnt signalling to protect the head region from posteriorisation and CEMs by Wnts by opposite concentration gradients of sFRPs against Wnts (Leyns et al., 1997; Wang et al., 1997; Pera and De Robertis, 2000; Shibata et al., 2005).”
BackgroundNalesso, G., Sherwood, J., Bertrand, J., Pap, T., Ramachandran, M., Bari, C. D., Pitzalis, C., & Dell’Accio, F. (2011) · The Journal of Cell Biology · doi:10.1083/jcb.201011051 · Cited by 202
“In addition, a loss of function polymorphism in the SFRP3 gene, encoding for a soluble Wnt inhibitor (Leyns et al., 1997; Wang et al., 1997), has been linked to an increased susceptibility to develop OA (Loughlin et al.”
BackgroundHead in the WNT: the molecular nature of Spemann’s head organizer
Niehrs, C. (1999) · Trends in Genetics · doi:10.1016/s0168-9525(99)01767-9 · Cited by 199
Bang, A. G., Papalopulu, N., Goulding, M., & Kintner, C. R. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9319 · Cited by 197
“frzB and sizzled (szl), which encode secreted proteins that act as antagonists of XWnt-8 signaling, are expressed during gastrulation in dorsal and ventral mesodermal domains, respectively (Leyns et al., 1997; Salic et al., 1997; Wang et al., 1997).”
Connective-tissue growth factor modulates WNT signalling and interacts with the WNT receptor complex
Mercurio, S., Latinkic, B., Itasaki, N., Krumlauf, R. K., & Smith, J. C. (2004) · Development · doi:10.1242/dev.01045 · Cited by 197
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“Frzb/sFRP3 binds to both Wnt-8 and Wnt-1 and acts as a functional inhibitor of Wnt-8 activity in Xenopus embryos (17, 18).”
Ligand Receptor Interactions in the Wnt Signaling Pathway inDrosophila
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Enomoto‐Iwamoto, M., Kitagaki, J., Koyama, E., Tamamura, Y., Wu, C., Kanatani, N., Koike, T., Okada, H., Komori, T., Yoneda, T., et al. (2002) · Developmental Biology · doi:10.1006/dbio.2002.0802 · Cited by 188
“All rights reserved. dral ossification (Hartmann and Tabin, 2000) and Wnt-8 is a target of, and is antagonized by, Frzb-1 (Leyns et al., 1997; Wang et al., 1997a).”
Zebrafish Dkk1 Functions in Forebrain Specification and Axial Mesendoderm Formation
Hashimoto, H., Itoh, M., Yamanaka, Y., Yamashita, S., Shimizu, T., Solnica-Krezel, L., Hibi, M., & Hirano, T. (2000) · Developmental Biology · doi:10.1006/dbio.1999.9537 · Cited by 184
Murine Cerberus Homologue mCer-1: A Candidate Anterior Patterning Molecule
Biben, C., Stanley, E. G., Fabri, L., Kotecha, S., Rhinn, M., Drinkwater, C. C., Lah, M. S., Wang, C.-C., Nash, A. D., Hilton, D. J., et al. (1998) · Developmental Biology · doi:10.1006/dbio.1997.8812 · Cited by 185
Yamamoto, A., Nagano, T., Takehara, S., Hibi, M., & Aizawa, S. (2005) · Cell · doi:10.1016/j.cell.2004.11.051 · Cited by 191
“Porcupine (Por)/Mom-1 is required sod et al., 1997; Leyns et al., 1997; Wang et al., 1997; for N-glycosylation and transportation of Wnt ligand (van Glinka et al., 1998; Thisse and Thisse, 1999).”
BackgroundGonzález‐Sancho, J. M., Brennan, K. R., Castelo‐Soccio, L. A., & Brown, A. M. C. (2004) · Molecular and Cellular Biology · doi:10.1128/mcb.24.11.4757-4768.2004 · Cited by 184
“5A) and are presumed to work by preventing interaction of the cognate receptors with ligand (11, 32, 44, 83, 90).”
BackgroundWnt Signaling in Vertebrate Axis SpecificationPreprint
Hikasa, H., & Sokol, S. Y. (2012) · Cold Spring Harbor Perspectives in Biology · doi:10.1101/cshperspect.a007955 · Cited by 178
“On the other hand, multiple Wnt antagonists, such as Frzb/Sfrp3, Crescent, Shisa, and Dkk1, are expressed in the head region (Leyns et al. 1997; Wang et al. 1997; Glinka et al. 1998; Shibata et al. 2005; Yamamoto et al. 2005).”
BackgroundWnt signaling in the vasculature
Goodwin, A. M., & D'Amore, P. A. (2002) · Angiogenesis · doi:10.1023/a:1021563510866 · Cited by 178
“FRP-3 binds to and inhibits secondary axisforming activity of Wnt-1 and Wnt-8 in Xenopus embryos [ 49 ], but blocks neither secondary axis activity ofWnt-5a nor downstream gene transcription in response to Wnt-3a or Wnt-11 [50].”
BackgroundAi, L., Tao, Q., Zhong, S., Fields, C. R., Kim, W.-J., Lee, M. W., Cui, Y., Brown, K. D., & Robertson, K. D. (2006) · Carcinogenesis · doi:10.1093/carcin/bgi379 · Cited by 177
BMP-2/-4 and Wnt-8 cooperatively pattern the Xenopus mesoderm
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“(Leyns et al., 1997; Wang et al., 1997).”
Ugolini, F., Charafe‐Jauffret, E., Bardou, V., Geneix, J., Adélaı̈de, J., Labat-Moleur, F., Penault-Llorca, F. M., Longy, M., Jacquemier, J. D., Birnbaum, D., et al. (2001) · Oncogene · doi:10.1038/sj.onc.1204706 · Cited by 176
“SFRP1 is a member of a group of soluble proteins, the soluble Frizzled-related proteins (SFRPs), also called secreted apoptosis-related proteins (SARPs) (Finch et al., 1997; Leyns et al., 1997; Rattner et al., 1997; Wang et al., 1997).”
BackgroundBaarsma, H. A., Königshoff, M., & Gosens, R. (2013) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2013.01.002 · Cited by 179
“…mutations in the LRP5 or LRP6 resulting in truncated proteins lacking the extracellular domain, induced a constitutively active canonical WNT signal, whereas the lack of the intracellular domain results in dominant negative receptors (G. Liu et al., 2003; Tamai et al., 2000; Wehrli et al., 2000).”
Background5 Cellular Mechanisms of Wingless/Wnt Signal Transduction
Dierick, H. A., & Bejsovec, A. (1998) · Current topics in developmental biology/Current Topics in Developmental Biology · doi:10.1016/s0070-2153(08)60381-6 · Cited by 170
Anterior Endomesoderm Specification inXenopusby Wnt/β-catenin and TGF-β Signalling Pathways
Zorn, A. M., Butler, K., & Gurdon, J. B. (1999) · Developmental Biology · doi:10.1006/dbio.1999.9257 · Cited by 170
Weinstein, D. C., & Hemmati‐Brivanlou, A. (1999) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.15.1.411 · Cited by 170
Roth, W., Wild‐Bode, C., Platten, M., Grimmel, C., Melkonyan, H. S., DICHGANS, J., & Weller, M. (2000) · Oncogene · doi:10.1038/sj.onc.1203783 · Cited by 169
“However, this signaling pathway can be modulated by a recently identi®ed group of soluble proteins, the soluble Frizzled-related proteins (sFRPs; secreted apoptosis-related proteins, SARPs) (Wang et al., 1997; Leyns et al., 1997; Rattner et al., 1997; Finch et al., 1997; Melkonyan et al., 1997).”
BackgroundHeller, R. S., Dichmann, D. S., Jensen, J. N., Miller, C., Wong, G. G., Madsen, O. D., & Serup, P. (2002) · Developmental Dynamics · doi:10.1002/dvdy.10157 · Cited by 167
“Additionally, in the mouse, four secreted Frizzled-related proteins (sFRPs) have been cloned (Rattner et al., 1997), some of which have been shown to bind Wnts and antagonize Wnt-mediated signaling (Wang et al., 1997a,b; Rattner et al., 1997).”
Background
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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