Notum deacylates Wnt proteins to suppress signalling activity
File(s)
Author(s)
Type
Journal Article
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.
Date Issued
2015-03-12
Date Acceptance
2015-01-26
Citation
Nature, 2015, 519 (7542), pp.187-192
ISSN
0028-0836
Publisher
Nature Research
Start Page
187
End Page
192
Journal / Book Title
Nature
Volume
519
Issue
7542
Copyright Statement
©2015 Macmillan Publishers Limited. All rights reserved. The final publication is available at Springer via https://doi.org/10.1038/nature14259
Identifier
http://gateway.webofknowledge.com/gateway/Gateway.cgi?GWVersion=2&SrcApp=PARTNER_APP&SrcAuth=LinksAMR&KeyUT=WOS:000350770500029&DestLinkType=FullRecord&DestApp=ALL_WOS&UsrCustomerID=1ba7043ffcc86c417c072aa74d649202
Subjects
Science & Technology
Multidisciplinary Sciences
Science & Technology - Other Topics
HEPARAN-SULFATE PROTEOGLYCANS
MORPHOGEN GRADIENT
CELL-SURFACE
DROSOPHILA
WINGLESS
HEDGEHOG
ACTIVATION
DPP
IDENTIFICATION
RECOGNITION
Publication Status
Published
Date Publish Online
2015-02-25