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Notum deacylates Wnt proteins to suppress signalling activity.

Kakugawa S, Langton PF, Zebisch M, Howell S, Chang TH, Liu Y, Feizi T, Bineva G, O'Reilly N, Snijders AP, Jones EY, Vincent JP
Nature 519 187-192 (2015)
Related entries: 4uyu, 4uyw, 4uyz, 4uz1, 4uz6, 4uz7, 4uz9, 4uza, 4uzj, 4uzk, 4uzl, 4uzq, 4wbh

Cited: 217 times
EuropePMC logo PMID: 25731175

Abstract

Signalling by Wnt proteins is finely balanced to ensure normal development and tissue homeostasis while avoiding diseases such as cancer. This is achieved in part by Notum, a highly conserved secreted feedback antagonist. Notum has been thought to act as a phospholipase, shedding glypicans and associated Wnt proteins from the cell surface. However, this view fails to explain specificity, as glypicans bind many extracellular ligands. Here we provide genetic evidence in Drosophila that Notum requires glypicans to suppress Wnt signalling, but does not cleave their glycophosphatidylinositol anchor. Structural analyses reveal glycosaminoglycan binding sites on Notum, which probably help Notum to co-localize with Wnt proteins. They also identify, at the active site of human and Drosophila Notum, a large hydrophobic pocket that accommodates palmitoleate. Kinetic and mass spectrometric analyses of human proteins show that Notum is a carboxylesterase that removes an essential palmitoleate moiety from Wnt proteins and thus constitutes the first known extracellular protein deacylase.

Articles - 4uz5 mentioned but not cited (2)

  1. Notum deacylates Wnt proteins to suppress signalling activity. Kakugawa S, Langton PF, Zebisch M, Howell S, Chang TH, Liu Y, Feizi T, Bineva G, O'Reilly N, Snijders AP, Jones EY, Vincent JP. Nature 519 187-192 (2015)
  2. Carboxylesterase Notum Is a Druggable Target to Modulate Wnt Signaling. Bayle ED, Svensson F, Atkinson BN, Steadman D, Willis NJ, Woodward HL, Whiting P, Vincent JP, Fish PV. J Med Chem 64 4289-4311 (2021)


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Articles citing this publication (145)

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