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J. Cell Biol. 162 (5): 899-908

Copyright © 2003 by the Rockefeller University Press.


Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3–independent ß-catenin degradation

Lilia Topol, Xueyuan Jiang, Hosoon Choi, Lisa Garrett-Beal, Peter J. Carolan, and Yingzi Yang

Genetic Disease Research Branch, National Human Genome Research Institute, National Institutes of Health, Bethesda, MD 20892

Address correspondence to Yingzi Yang, Genetic Disease Research Branch, National Human Genome Research Institute, NIH, 49 Convent Dr., Room 4A68, Bethesda, MD 20892. Tel: (301) 402-2034. Fax: (301) 402-2170. email: yyang{at}

Abstract: Wnts are secreted signaling molecules that can transduce their signals through several different pathways. Wnt-5a is considered a noncanonical Wnt as it does not signal by stabilizing ß-catenin in many biological systems. We have uncovered a new noncanonical pathway through which Wnt-5a antagonizes the canonical Wnt pathway by promoting the degradation of ß-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and ß-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote ß-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.

Key Words: limb; chondrogenesis; cancer; Siah2; APC

Xueyuan Jiang's present address is Dept. of Biochemistry and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, People's Republic of China.

Abbreviations used in this paper: AER, apical ectodermal ridge; CEF, chick embryonic fibroblast; CsA, Cyclosporin A.

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Foxf1 and Foxf2 control murine gut development by limiting mesenchymal Wnt signaling and promoting extracellular matrix production.
M. Ormestad, J. Astorga, H. Landgren, T. Wang, B. R. Johansson, N. Miura, and P. Carlsson (2006)
Development 133, 833-843
   Abstract »    Full Text »    PDF »
The Wnt-inducible Transcription Factor Twist1 Inhibits Chondrogenesis.
M. I. Reinhold, R. M. Kapadia, Z. Liao, and M. C. Naski (2006)
J. Biol. Chem. 281, 1381-1388
   Abstract »    Full Text »    PDF »
Up-regulation of {beta}-catenin by a viral oncogene correlates with inhibition of the seven in absentia homolog 1 in B lymphoma cells.
K. L. Jang, J. Shackelford, S. Y. Seo, and J. S. Pagano (2005)
PNAS 102, 18431-18436
   Abstract »    Full Text »    PDF »
Wnt Proteins Prevent Apoptosis of Both Uncommitted Osteoblast Progenitors and Differentiated Osteoblasts by {beta}-Catenin-dependent and -independent Signaling Cascades Involving Src/ERK and Phosphatidylinositol 3-Kinase/AKT.
M. Almeida, L. Han, T. Bellido, S. C. Manolagas, and S. Kousteni (2005)
J. Biol. Chem. 280, 41342-41351
   Abstract »    Full Text »    PDF »
Importance of P-Cadherin, {beta}-Catenin, and Wnt5a/Frizzled for Progression of Melanocytic Tumors and Prognosis in Cutaneous Melanoma.
I. M. Bachmann, O. Straume, H. E. Puntervoll, M. B. Kalvenes, and L. A. Akslen (2005)
Clin. Cancer Res. 11, 8606-8614
   Abstract »    Full Text »    PDF »
Wnt-5a Protein Expression in Primary Dukes B Colon Cancers Identifies a Subgroup of Patients with Good Prognosis.
J. Dejmek, A. Dejmek, A. Safholm, A. Sjolander, and T. Andersson (2005)
Cancer Res. 65, 9142-9146
   Abstract »    Full Text »    PDF »
Glycogen Synthase Kinase 3{beta} Functions To Specify Gene-Specific, NF-{kappa}B-Dependent Transcription.
K. A. Steinbrecher, W. Wilson III, P. C. Cogswell, and A. S. Baldwin (2005)
Mol. Cell. Biol. 25, 8444-8455
   Abstract »    Full Text »    PDF »
Estrogen down-regulation of the corepressor N-CoR: Mechanism and implications for estrogen derepression of N-CoR-regulated genes.
J. Frasor, J. M. Danes, C. C. Funk, and B. S. Katzenellenbogen (2005)
PNAS 102, 13153-13157
   Abstract »    Full Text »    PDF »
Hotelling's T2 multivariate profiling for detecting differential expression in microarrays.
Y. Lu, P.-Y. Liu, P. Xiao, and H.-W. Deng (2005)
Bioinformatics 21, 3105-3113
   Abstract »    Full Text »    PDF »
From The Cover: Uterine Wnt/{beta}-catenin signaling is required for implantation.
O. A. Mohamed, M. Jonnaert, C. Labelle-Dumais, K. Kuroda, H. J. Clarke, and D. Dufort (2005)
PNAS 102, 8579-8584
   Abstract »    Full Text »    PDF »
Developmental Regulation of Wnt/{beta}-Catenin Signals Is Required for Growth Plate Assembly, Cartilage Integrity, and Endochondral Ossification.
Y. Tamamura, T. Otani, N. Kanatani, E. Koyama, J. Kitagaki, T. Komori, Y. Yamada, F. Costantini, S. Wakisaka, M. Pacifici, et al. (2005)
J. Biol. Chem. 280, 19185-19195
   Abstract »    Full Text »    PDF »
The Loss of Glypican-3 Induces Alterations in Wnt Signaling.
H. H. Song, W. Shi, Y.-Y. Xiang, and J. Filmus (2005)
J. Biol. Chem. 280, 2116-2125
   Abstract »    Full Text »    PDF »
Noncanonical Wnt signaling regulates midline convergence of organ primordia during zebrafish development.
T. Matsui, A. Raya, Y. Kawakami, C. Callol-Massot, J. Capdevila, C. Rodriguez-Esteban, and J. C. Izpisua Belmonte (2005)
Genes & Dev. 19, 164-175
   Abstract »    Full Text »    PDF »

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