Wnt-5a Inhibits the Canonical Wnt Pathway by Promoting GSK-3-Independent β-Catenin Degradation

• Published in: The Journal of cell biology Vol. 162; no. 5; pp. 899 - 908
• Main Authors: Topol, Lilia, Jiang, Xueyuan, Choi, Hosoon, Garrett-Beal, Lisa, Carolan, Peter J., Yang, Yingzi
• Format: Journal Article
• Language: English
• Published: United States Rockefeller University Press 01.09.2003; The Rockefeller University Press
• Subjects: Adenomatous Polyposis Coli Protein - metabolism; Animals; beta Catenin; Calcium-Calmodulin-Dependent Protein Kinase Type 2; Calcium-Calmodulin-Dependent Protein Kinases - metabolism; Cell division; Cell Line; Cell Line, Tumor; Cell lines; Cells; Chondrocytes; Chondrogenesis; Culture Techniques; Cytoskeletal Proteins - metabolism; DNA-Binding Proteins - metabolism; Embryo, Mammalian - anatomy & histology; Embryo, Mammalian - physiology; Embryonic Structures - metabolism; Embryos; Enzyme Activation; Gene Expression Regulation; Genes, Reporter; Glycogen Synthase Kinase 3 - metabolism; HEK293 cells; Humans; Limb buds; Mice; Mice, Transgenic; NFATC Transcription Factors; Nuclear Proteins - metabolism; Plasmids; Proto-Oncogene Proteins - genetics; Proto-Oncogene Proteins - metabolism; Signal Transduction - physiology; Trans-Activators - metabolism; Transcription Factors - metabolism; Transfection; Tumors; Ubiquitin-Protein Ligases; Wnt Proteins; Wnt-5a Protein
• ISSN: 0021-9525; 1540-8140
• DOI: 10.1083/jcb.200303158

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 β-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 β-catenin. This pathway is Siah2 and APC dependent, but GSK-3 and β-TrCP independent. Furthermore, we provide evidence that Wnt-5a also acts in vivo to promote β-catenin degradation in regulating mammalian limb development and possibly in suppressing tumor formation.