The DOI matches its Crossref record; 59 of the 59 references it cites were found in a registry or an index.
Purified Wnt5a Protein Activates or Inhibits β-Catenin–TCF Signaling Depending on Receptor Context
Open accessAbstract
The Wnts comprise a large class of secreted proteins that control essential developmental processes such as embryonic patterning, cell growth, migration, and differentiation. In the most well-understood "canonical" Wnt signaling pathway, Wnt binding to Frizzled receptors induces beta-catenin protein stabilization and entry into the nucleus, where it complexes with T-cell factor/lymphoid enhancer factor transcription factors to affect the transcription of target genes. In addition to the canonical pathway, evidence for several other Wnt signaling pathways has accumulated, in particular for Wnt5a, which has therefore been classified as a noncanonical Wnt family member. To study the alternative mechanisms by which Wnt proteins signal, we purified the Wnt5a protein to homogeneity. We find that purified Wnt5a inhibits Wnt3a protein-induced canonical Wnt signaling in a dose-dependent manner, not by influencing beta-catenin levels but by downregulating beta-catenin-induced reporter gene expression. The Wnt5a signal is mediated by the orphan tyrosine kinase Ror2, is pertussis toxin insensitive, and does not influence cellular calcium levels. We show that in addition to its inhibitory function, Wnt5a can also activate beta-catenin signaling in the presence of the appropriate Frizzled receptor, Frizzled 4. Thus, this study shows for the first time that a single Wnt ligand can initiate discrete signaling pathways through the activation of two distinct receptors. Based on these and additional observations, we propose a model wherein receptor context dictates Wnt signaling output. In this model, signaling by different Wnt family members is not intrinsically regulated by the Wnt proteins themselves but by receptor availability.
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1 retracted
Hong, K., Hinck, L., Nishiyama, M., Poo, M.-M., Tessier-Lavigne, M., & Stein, E. (1999) · Cell · doi:10.1016/s0092-8674(00)80804-1 · Cited by 683
RetractedImproved Prediction of Signal Peptides: SignalP 3.0
Dyrløv Bendtsen, J., Nielsen, H., von Heijne, G., & Brunak, S. (2004) · Journal of Molecular Biology · doi:10.1016/j.jmb.2004.05.028 · Cited by 6,350
The Wnt Signaling Pathway in Development and Disease
Logan, C. Y., & Nusse, R. (2004) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.20.010403.113126 · Cited by 5,325
Self-citationWnt signalling in stem cells and cancer
Reya, T., & Clevers, H. (2005) · Nature · doi:10.1038/nature03319 · Cited by 3,666
The Molecular Biology of Axon Guidance
Tessier-Lavigne, M., & Goodman, C. S. (1996) · Science · doi:10.1126/science.274.5290.1123 · Cited by 3,278
Polakis, P. (2000) · Genes & Development · doi:10.1101/gad.14.15.1837 · Cited by 3,183
Wnt proteins are lipid-modified and can act as stem cell growth factors
Willert, K., Brown, J. D., Danenberg, E., Duncan, A. W., Weissman, I. L., Reya, T., Yates, J. R., & Nusse, R. (2003) · Nature · doi:10.1038/nature01611 · Cited by 2,257
Self-citationG-protein-coupled receptor heterodimerization modulates receptor function
Jordan, B. A., & Devi, L. A. (1999) · Nature · doi:10.1038/21441 · Cited by 1,166
LDL-receptor-related proteins in Wnt signal transduction
Tamai, K., Semenov, M., Kato, Y., Spokony, R., Liu, C., Katsuyama, Y., Hess, F., Saint-Jeannet, J.-P., & He, X. (2000) · Nature · doi:10.1038/35035117 · Cited by 1,128
A Wnt5a pathway underlies outgrowth of multiple structures in the vertebrate embryo
Yamaguchi, T. P., Bradley, A., McMahon, A. P., & Jones, S. (1999) · Development · doi:10.1242/dev.126.6.1211 · Cited by 970
Wnt5a signaling directly affects cell motility and invasion of metastatic melanoma
Weeraratna, A. T., Jiang, Y., Hostetter, G., Rosenblatt, K., Duray, P., Bittner, M., & Trent, J. M. (2002) · Cancer Cell · doi:10.1016/s1535-6108(02)00045-4 · Cited by 959
Kühl, M., Sheldahl, L. C., Park, M., Miller, J. R., & Moon, R. T. (2000) · Trends in Genetics · doi:10.1016/s0168-9525(00)02028-x · Cited by 861
The receptor tyrosine kinase Ror2 is involved in non‐canonical Wnt5a/JNK signalling pathway
Oishi, I., Suzuki, H., Onishi, N., Takada, R., Kani, S., Ohkawara, B., Koshida, I., Suzuki, K., Yamada, G., Schwabe, G. C., et al. (2003) · Genes to Cells · doi:10.1046/j.1365-2443.2003.00662.x · Cited by 780
Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent β-catenin degradation
Topol, L., Jiang, X., Choi, H., Garrett-Beal, L., Carolan, P. J., & Yang, Y. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200303158 · Cited by 724
Slusarski, D. C., Corces, V. G., & Moon, R. T. (1997) · Nature · doi:10.1038/37138 · Cited by 680 · cited 1×
“In a variety of organisms and assays, Ca2þ signaling induced by Wnts has consistently been shown to be PTX sensitive, as the Fz receptor described as transmitting the inhibitory Wnt signal (RFz2) is thought to be coupled to a PTX-sensitive G protein [8,37,38].”
BackgroundIshitani, T., Ninomiya-Tsuji, J., Nagai, S.-I., Nishita, M., Meneghini, M., Barker, N., Waterman, M., Bowerman, B., Clevers, H., Shibuya, H., et al. (1999) · Nature · doi:10.1038/21674 · Cited by 621
Mode of proviral activation of a putative mammary oncogene (int-1) on mouse chromosome 15
Nusse, R., van Ooyen, A., Cox, D., Fung, Y. K. T., & Varmus, H. (1984) · Nature · doi:10.1038/307131a0 · Cited by 612
Self-citationIshitani, T., Kishida, S., Hyodo-Miura, J., Ueno, N., Yasuda, J., Waterman, M., Shibuya, H., Moon, R. T., Ninomiya-Tsuji, J., & Matsumoto, K. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.1.131-139.2003 · Cited by 541
Kühl, M., Sheldahl, L. C., Malbon, C. C., & Moon, R. T. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.275.17.12701 · Cited by 517
Tao, Q., Yokota, C., Puck, H., Kofron, M., Birsoy, B., Yan, D., Asashima, M., Wylie, C. C., Lin, X., & Heasman, J. (2005) · Cell · doi:10.1016/j.cell.2005.01.013 · Cited by 510
A Member of the Frizzled Protein Family Mediating Axis Induction by Wnt-5A
He, X., Saint-Jeannet, J.-P., Wang, Y., Nathans, J., Dawid, I., & Varmus, H. (1997) · Science · doi:10.1126/science.275.5306.1652 · Cited by 492
Mutant frizzled-4 disrupts retinal angiogenesis in familial exudative vitreoretinopathy
Robitaille, J., MacDonald, M. L. E., Kaykas, A., Sheldahl, L. C., Zeisler, J., Dubé, M.-P., Zhang, L.-H., Singaraja, R. R., Guernsey, D. L., Zheng, B., et al. (2002) · Nature Genetics · doi:10.1038/ng957 · Cited by 482
Sheldahl, L. C., Park, M., Malbon, C. C., & Moon, R. T. (1999) · Current Biology · doi:10.1016/s0960-9822(99)80310-8 · Cited by 475
Yamanaka, H., Moriguchi, T., Masuyama, N., Kusakabe, M., Hanafusa, H., Takada, R., Takada, S., & Nishida, E. (2002) · EMBO reports · doi:10.1093/embo-reports/kvf008 · Cited by 451
Transformation by Wnt family proteins correlates with regulation of beta-catenin.
Shimizu, H., Julius, M. A., Giarrè, M., Zheng, Z., Brown, A. M. C., & Kitajewski, J. (1997) · PubMed · Cited by 409
Torres, M. A., Yang-Snyder, J. A., Purcell, S. M., DeMarais, A. A., McGrew, L. L., & Moon, R. T. (1996) · The Journal of cell biology · doi:10.1083/jcb.133.5.1123 · Cited by 405
Modulation of Embryonic Intracellular Ca2+Signaling byWnt-5A
Slusarski, D. C., Yang-Snyder, J., Busa, W. B., & Moon, R. T. (1997) · Developmental Biology · doi:10.1006/dbio.1996.8463 · Cited by 404
Heterodimerization of μ and δ Opioid Receptors: A Role in Opiate Synergy
Gomes, I., Jordan, B. A., Gupta, A., Trapaidze, N., Nagy, V., & Devi, L. A. (2000) · The Journal of Neuroscience · doi:10.1523/jneurosci.20-22-j0007.2000 · Cited by 403
Hsieh, J.-C., Rattner, A., Smallwood, P. M., & Nathans, J. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.7.3546 · Cited by 349
Differential transformation of mammary epithelial cells by Wnt genes.
Wong, G. T., Gavin, B. J., & McMahon, A. P. (1994) · Molecular and Cellular Biology · doi:10.1128/mcb.14.9.6278 · Cited by 339
Marlow, F., Topczewski, J., Sepich, D., & Solnica-Krezel, L. (2002) · Current Biology · doi:10.1016/s0960-9822(02)00864-3 · Cited by 337
Dishevelled 2 Recruits ß-Arrestin 2 to Mediate Wnt5A-Stimulated Endocytosis of Frizzled 4
Chen, W., ten Berge, D., Brown, J., Ahn, S., Hu, L. A., Miller, W. E., Caron, M. G., Barak, L. S., Nusse, R., & Lefkowitz, R. J. (2003) · Science · doi:10.1126/science.1082808 · Cited by 334
Self-citationWnt5a inhibits B cell proliferation and functions as a tumor suppressor in hematopoietic tissue
Liang, H., Chen, Q., Coles, A. H., Anderson, S. J., Pihan, G., Bradley, A., Gerstein, R., Jurecic, R., & Jones, S. N. (2003) · Cancer Cell · doi:10.1016/s1535-6108(03)00268-x · Cited by 329
Wnt signals are transmitted through N‐terminally dephosphorylated β‐catenin
Staal, F. J. T., van Noort, M., Strous, G. J., & Clevers, H. C. (2002) · EMBO reports · doi:10.1093/embo-reports/kvf002 · Cited by 316
Du, S. J., Purcell, S. M., Christian, J. L., McGrew, L. L., & Moon, R. T. (1995) · Molecular and Cellular Biology · doi:10.1128/mcb.15.5.2625 · Cited by 314
Umbhauer, M. (2000) · The EMBO Journal · doi:10.1093/emboj/19.18.4944 · Cited by 304
Mouse Ror2 receptor tyrosine kinase is required for the heart development and limb formation
Takeuchi, S., Takeda, K., Oishi, I., Nomi, M., Ikeya, M., Itoh, K., Tamura, S., Ueda, T., Hatta, T., Otani, H., et al. (2000) · Genes to Cells · doi:10.1046/j.1365-2443.2000.00300.x · Cited by 222
Kühl, M., Geis, K., Sheldahl, L. C., Pukrop, T., Moon, R. T., & Wedlich, D. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(01)00416-6 · Cited by 220
Ishitani, T., Ninomiya-Tsuji, J., & Matsumoto, K. (2003) · Molecular and Cellular Biology · doi:10.1128/mcb.23.4.1379-1389.2003 · Cited by 212 · cited 1×
“This phosphorylation of TCF/LEF prevents the b-catenin–TCF/LEF transcriptional complex from binding to DNA [17,18,36].”
BackgroundHikasa, H., Shibata, M., Hiratani, I., & Taira, M. (2002) · Development · doi:10.1242/dev.129.22.5227 · Cited by 202
Signaling of Rat Frizzled-2 Through Phosphodiesterase and Cyclic GMP
Ahumada, A., Slusarski, D. C., Liu, X., Moon, R. T., Malbon, C. C., & Wang, H.-Y. (2002) · Science · doi:10.1126/science.1073776 · Cited by 178
A C. elegans Ror receptor tyrosine kinase regulates cell motility and asymmetric cell division
Forrester, W. C., Dell, M., Perens, E., & Garriga, G. (1999) · Nature · doi:10.1038/23722 · Cited by 175
Kaykas, A., Yang-Snyder, J., Héroux, M., Shah, K. V., Bouvier, M., & Moon, R. T. (2004) · Nature Cell Biology · doi:10.1038/ncb1081 · Cited by 174
Expression of the receptor tyrosine kinase genes, Ror1 and Ror2, during mouse development
Matsuda, T., Nomi, M., Ikeya, M., Kani, S., Oishi, I., Terashima, T., Takada, S., & Minami, Y. (2001) · Mechanisms of Development · doi:10.1016/s0925-4773(01)00383-5 · Cited by 156
Imaging Synapse Formation during Thymocyte Selection
Ehrlich, L. I. R., Ebert, P. J. R., Wu, L. C., Krummel, M. F., Owen, J. J. T., & Davis, M. M. (2002) · Immunity · doi:10.1016/s1074-7613(02)00299-6 · Cited by 143
Liu, X., Liu, T., Slusarski, D. C., Yang-Snyder, J., Malbon, C. C., Moon, R. T., & Wang, H. (1999) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.96.25.14383 · Cited by 133
The Frizzled CRD domain is conserved in diverse proteins including several receptor tyrosine kinases
Xu, Y. K., & Nusse, R. (1998) · Current Biology · doi:10.1016/s0960-9822(98)70262-3 · Cited by 130
Self-citationWnt Activates the Tak1/Nemo-like Kinase Pathway
Smit, L., Baas, A. F., Kuipers, J., Korswagen, H. C., van de Wetering, M., & Clevers, H. C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m307801200 · Cited by 111
Yoda, A., Oishi, I., & Minami, Y. (2003) · Journal of Receptors and Signal Transduction · doi:10.1081/rrs-120018757 · Cited by 106
Weidinger, G., & Moon, R. T. (2003) · The Journal of Cell Biology · doi:10.1083/jcb.200307181 · Cited by 101
Low expression of Wnt-5a gene is associated with high-risk neuroblastoma
Blanc, É., Roux, G. L., Bénard, J., & Raguénez, G. (2004) · Oncogene · doi:10.1038/sj.onc.1208255 · Cited by 91
Liu, G., Bafico, A., & Aaronson, S. A. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.9.3475-3482.2005 · Cited by 85
The Caenorhabditis elegans Ror RTK CAM-1 Inhibits EGL-20/Wnt Signaling in Cell Migration
Forrester, W. C., Kim, C., & Garriga, G. (2004) · Genetics · doi:10.1534/genetics.104.031781 · Cited by 82
WNT5A expression in human breast cancer.
Leris, A. C. A., Roberts, T. R., Jiang, W. G., Newbold, R. F., & Mokbel, K. (2005) · PubMed · Cited by 81
Murphy, L. L. S., & Hughes, C. C. W. (2002) · The Journal of Immunology · doi:10.4049/jimmunol.169.7.3717 · Cited by 78
Functional analysis of the domains of the C. elegans Ror receptor tyrosine kinase CAM-1
Kim, C., & Forrester, W. C. (2003) · Developmental Biology · doi:10.1016/j.ydbio.2003.09.007 · Cited by 73
Fradkin, L. G., Noordermeer, J. N., & Nusse, R. (1995) · Developmental Biology · doi:10.1006/dbio.1995.1072 · Cited by 69
Self-citationA Mode of Regulation of β-Catenin Signaling Activity in Xenopus Embryos Independent of Its Levels
Guger, K. A., & Gumbiner, B. M. (2000) · Developmental Biology · doi:10.1006/dbio.2000.9770 · Cited by 65
Regulated expression of Wnt family members during proliferation of C57mg mammary cells.
Olson, D. J., & Papkoff, J. S. (1994) · PubMed · Cited by 59
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Wnt/β-Catenin Signaling in Development and Disease
Clevers, H. (2006) · Cell · doi:10.1016/j.cell.2006.10.018 · Cited by 5,568
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Gordon, M. D., & Nusse, R. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.r600015200 · Cited by 1,333
Self-citationFunction and biological roles of the Dickkopf family of Wnt modulators
Niehrs, C. (2006) · Oncogene · doi:10.1038/sj.onc.1210054 · Cited by 995
Metadata
- Authors
- Mikels, A. J., & Nusse, R.
- Venue
- PLoS Biology
- Publisher
- Public Library of Science (PLoS)
- Published
- 2006-04-04
- Volume
- 4
- Issue
- 4
- Pages
- e115
- ISSN
- 1544-9173 (ISSN-L)
- 1545-7885
- OpenAlex
- W2009684443
- Cited by
- 1,252
- References
- 59
- FWCI
- 30.70
- Type
- journal article
- Language
- en
- Open access
- gold
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