IDEAS home Printed from https://ideas.repec.org/a/nat/nature/v519y2015i7542d10.1038_nature14259.html
   My bibliography  Save this article

Notum deacylates Wnt proteins to suppress signalling activity

Author

Listed:
  • Satoshi Kakugawa

    (MRC’s National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK)

  • Paul F. Langton

    (MRC’s National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK)

  • Matthias Zebisch

    (Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK
    Present address: Evotec (UK) Ltd, 114 Innovation Drive, Milton Park, Abingdon, Oxfordshire OX14 4RZ, UK.)

  • Steven A. Howell

    (MRC’s National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK)

  • Tao-Hsin Chang

    (Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK)

  • Yan Liu

    (Glycosciences Laboratory, Imperial College London, Du Cane Road, London W12 0NN, UK)

  • Ten Feizi

    (Glycosciences Laboratory, Imperial College London, Du Cane Road, London W12 0NN, UK)

  • Ganka Bineva

    (Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK)

  • Nicola O’Reilly

    (Cancer Research UK, London Research Institute, 44 Lincoln’s Inn Fields, London WC2A 3LY, UK)

  • Ambrosius P. Snijders

    (Cancer Research UK, Clare Hall Laboratories, Blanche Lane, South Mimms, Potters Bar, Hertfordshire EN6 3LD, UK)

  • E. Yvonne Jones

    (Wellcome Trust Centre for Human Genetics, University of Oxford, Roosevelt Drive, Oxford OX3 7BN, UK)

  • Jean-Paul Vincent

    (MRC’s National Institute for Medical Research, The Ridgeway, Mill Hill, London NW7 1AA, UK)

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.

Suggested Citation

  • Satoshi Kakugawa & Paul F. Langton & Matthias Zebisch & Steven A. Howell & Tao-Hsin Chang & Yan Liu & Ten Feizi & Ganka Bineva & Nicola O’Reilly & Ambrosius P. Snijders & E. Yvonne Jones & Jean-Paul V, 2015. "Notum deacylates Wnt proteins to suppress signalling activity," Nature, Nature, vol. 519(7542), pages 187-192, March.
    • Handle: RePEc:nat:nature:v:519:y:2015:i:7542:d:10.1038_nature14259
    DOI: 10.1038/nature14259
    as

    Download full text from publisher

    File URL: https://www.nature.com/articles/nature14259
    File Function: Abstract
    Download Restriction: Access to the full text of the articles in this series is restricted.
    File URL: https://libkey.io/10.1038/nature14259?utm_source=ideas
    LibKey link: if access is restricted and if your library uses this service, LibKey will redirect you to where you can use your library subscription to access this item
    ---><---

    As the access to this document is restricted, you may want to search for a different version of it.

    Citations

    Citations are extracted by the CitEc Project, subscribe to its RSS feed for this item.
    as


    Cited by:

    1. Mijeong Kim & Yu Jin Jang & Muyoung Lee & Qingqing Guo & Albert J. Son & Nikita A. Kakkad & Abigail B. Roland & Bum-Kyu Lee & Jonghwan Kim, 2024. "The transcriptional regulatory network modulating human trophoblast stem cells to extravillous trophoblast differentiation," Nature Communications, Nature, vol. 15(1), pages 1-18, December.

    More about this item

    Statistics

    Access and download statistics

    Corrections

    All material on this site has been provided by the respective publishers and authors. You can help correct errors and omissions. When requesting a correction, please mention this item's handle: RePEc:nat:nature:v:519:y:2015:i:7542:d:10.1038_nature14259. See general information about how to correct material in RePEc.

    If you have authored this item and are not yet registered with RePEc, we encourage you to do it here. This allows to link your profile to this item. It also allows you to accept potential citations to this item that we are uncertain about.

    We have no bibliographic references for this item. You can help adding them by using this form .

    If you know of missing items citing this one, you can help us creating those links by adding the relevant references in the same way as above, for each refering item. If you are a registered author of this item, you may also want to check the "citations" tab in your RePEc Author Service profile, as there may be some citations waiting for confirmation.

    For technical questions regarding this item, or to correct its authors, title, abstract, bibliographic or download information, contact: Sonal Shukla or Springer Nature Abstracting and Indexing (email available below). General contact details of provider: http://www.nature.com .

    Please note that corrections may take a couple of weeks to filter through the various RePEc services.

    IDEAS is a RePEc service. RePEc uses bibliographic data supplied by the respective publishers.