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Switching off WNT with precision

Nature Reviews Molecular Cell Biology volume 16, pages 204–205 (2015)Cite this article

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It has been suggested previously that Notum functions by cleaving the GPI (glycosylphosphatidylinositol) anchor of glypicans (which are membrane heparan sulfate proteoglycans (HSPGs)) and releasing them from the cell surface (a process known as shedding), thus affecting their ability to stabilize and/or retain WNT proteins at the cell surface. However, glypican-based interactions modulate signalling from several ligands other than WNT (including TGF-β, Hedgehog and fibroblast growth factor (FGF)), prompting the question of how Notum can be a feedback inhibitor that is specific for WNT signalling.

Intriguingly, in contrast to previous results, the authors found that Notum was unable to cleave the GPI anchor of glypicans when using cell extracts. They went on to investigate the role of glypicans in the suppression of Wingless (Wg, the main WNT in Drosophila melanogaster) signalling by Notum. The authors found that Notum-mediated repression was reduced in cells lacking glypican. However, expression of a glypican in which the GPI anchor was replaced with a non-cleavable transmembrane domain restored Notum-mediated repression of Wg signalling. Thus, Notum does not function in WNT repression by shedding glypicans.

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References

  1. Kakugawa, S. et al. Notum deacylates Wnt proteins to suppress signalling activity. Nature http://dx.doi.org/10.1038/nature14259 (2015)

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  1. Kim Baumann
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Related links in Nature Research

Niehrs, C. The complex world of WNT receptor signalling. Nature Rev. Mol. Cell Biol. 13, 767–779 (2012)

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Baumann, K. Switching off WNT with precision. Nat Rev Mol Cell Biol 16, 204–205 (2015). https://doi.org/10.1038/nrm3971

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