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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}nhgri.nih.gov

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

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

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