Developmental Biology

Uncleavable Notch Suppresses Wnt

Science's STKE  05 Apr 2005:
Vol. 2005, Issue 278, pp. tw127
DOI: 10.1126/stke.2782005tw127

Notch and Wnt [Wingless (Wg) in flies] are both pathways involved in developmental processes. Both pathways result in changes in gene expression. For Notch, this transcriptional activation occurs following cleavage of the Notch receptor to produce a soluble intracellular domain (NICD) that interacts with the transcriptional regulator Suppressor of Hairless [Su(H)]. Hayward et al. report that an uncleavable Notch chimeric receptor (Notch intracellular domain fused to a receptor tyrosine kinase transmembrane and extracellular domain) TNotch suppressed the effects of constitutively activated Wnt signaling, suggesting a new mechanism by which Notch and Wnt pathways crosstalk. TNotch cannot activate Notch target genes and does not signal through Su(H). In the Drosophila wing, TNotch prevented the formation of extra wing tissue and suppressed the elevation observed in the expression of Wnt target genes in response to nonphosphorylatable and thus constitutively stabilized Armadillo (Drosophila β-catenin) Arms10 or ectopic expression of wg. Ectopic expression of Notch or TNotch with Arms10 resulted in decreased abundance of Arms10 and endogenous Armadillo based on Western blotting and immunofluorescence. These in vivo data were supported by experiments in Drosophila cultured cells and were observed for the mammalian homologs in transfected human embryonic kidney cells (HEK293). In both cell systems, Notch or uncleavable Notch (fly or mouse) suppressed Wnt reporter gene expression. A direct interaction between Notch and Armadillo is supported by the observation that the two proteins were coimmunoprecipitated from fly embryos. Thus, Notch and Wnt appear to have a point of crosstalk at the level of Armadillo that allows Notch to inhibit Wnt signaling.

P. Hayward, K. Brennan, P. Sanders, T. Balayo, R. DasGupta, N. Perrimon, A. M. Arias, Notch modulates Wnt signalling by associating with Armadillo/β-catenin and regulating its transcriptional activity. Development 132, 1819-1830 (2005). [PubMed]