Wnt Versus Wnt

In the canonical Wnt signaling pathway, Wnts cause stabilization of β-catenin and consequent changes in gene expression. But not all Wnts appear to signal in this way. Developmental actions of Wnt-5, for example, appear not to be mediated by β-catenin, and now two papers show that Wnt-5 actually antagonizes canonical Wnt signaling. Westfall et al. explored developmental roles of WNt-5 in zebrafish. The dorsalization defects they observed when expression of maternal and zygotic Wnt-5 was removed were similar to effects of activation of canonical Wnt-β-catenin signaling and were associated with accumulation of β-catenin. Loss of Wnt-5 caused decreased Ca 2+ release, and overexpression of Ca 2+ -calmodulin-dependent protein kinase II partially rescued the effects of Wnt-5 mutation. Thus, the authors conclude that Wnt-5 actually antagonizes the effects of canonical Wnts, possibly by a Ca 2+ -mediated signal. Topol et al. offer an alternative mechanism. In cultured mammalian 293 cells and in a human colon cancer cell line, ectopic expression of Wnt-5a antagonized canonical Wnt signaling and caused degradation of β-catenin. Their analysis, however, indicated that Wnt-5's effects were largely independent of Ca 2+ -mediated signals. Rather, they propose that Wnt-5a may increase expression of Siah2, a component of the proteasome, which mediates degradation of β-catenin. In 293 cells, dominant-negative Siah2 reduced the effects of Wnt-5a on β-catenin signaling, and ectopic expression of Wnt-5a increased expression of Siah2. In Wnt-5a knockout mice, β-catenin also accumulated in the distal limb bud during development. Thus, in limb buds lacking Wnt-5a, unchecked canonical Wnt signaling may cause developmental abnormalities. Consistent with this idea, chondorgenesis is inhibited in Wnt5a –/– limbs, but was partially rescued by grafted chick embryonic fibroblast cells engineered to express a secreted antagonist of Wnt signaling. Both groups agree that proper development appears to require a balance of opposing Wnt signals and that disruption of that balance could contribute to abnormal canonical Wnt signaling, which is implicated in formation of some human cancers. T. A. Westfall, R. Brimeyer, J. Twedt, J. Gladon, A. Olberding, M. Furutani-Seiki, D. C. Slusarski, Wnt-5/pipetail functions in vertebrate axis formation as a negative regulator of Wnt/β-catenin activity. J. Cell Biol. 162 , 889-898 (2003). [Abstract] [Full Text] L. Topol, X. Jiang, H. Choi, L. Garrett-Beal, P. J. Carolan, Y. Yang, Wnt-5a inhibits the canonical Wnt pathway by promoting GSK-3-independent β-catenin degradation. J. Cell Biol. 162 , 899-908 (2003). [Abstract] [Full Text]