Wnt Signaling Model Challenged

Science's STKE  22 Oct 2002:
Vol. 2002, Issue 155, pp. tw387-TW387
DOI: 10.1126/stke.2002.155.tw387

The wingless(Wg)-Int1 (Wnt) proteins are important regulators of development. Most current models of Wnt signaling propose that transcriptional regulation through the Wnt pathway results from accumulation of β-catenin in the nucleus where it interacts with TCF-LEF transcription factors to regulate target genes. Studies reported by Chan and Struhl now challenge this view, suggesting instead that β-catenin may have its regulatory effects outside the nucleus independent of transcriptional complexes that bind target promoters. Their results in Drosophila show that forms of β-catenin that are targeted to the cell membrane and excluded from the nucleus still transmit Wg signals that regulate transcription of target genes. In fact, targeting of β-catenin to the nucleus inhibited its transcriptional effects. They also found that addition of viral VP16 activation domain could not substitute for the COOH-terminal domain of β-catenin (which is thought to mediate its effects on transcriptional activation), but that such modification of the Drosophila TCF homolog did suffice to allow activation of target genes. The authors propose that rather than acting as part of a nuclear complex that regulates target genes, β-catenin may act to remove a repressor form of TCF from the nucleus or function in the cytoplasm to promote formation of activated TCF.

S.-K. Chan, G. Struhl, Evidence that Armadillo transduces wingless by mediating nuclear export or cytosolic activation of pangolin. Cell 111, 265-280 (2002). [Online Journal]