The result could have implications for the treatment of diseases including cancer and Alzheimer's disease. Signalling by Wnt proteins is finely balanced to ensure normal development and healthy adulthood. The teams in Oxford and Mill Hill joined forces to use methods ranging from Drosophila fruit fly genetics to structure-function analysis and enzymology to investigate how Wnt proteins are regulated by a secreted protein called Notum. The multi-disciplinary study revealed that Notum can bind to a fatty acid chain Wnt needs to interact with its receptor, and snip it off, thereby reducing the signalling activity of the Wnt proteins – Notum is a Wnt-specific deacylase. This finding opens up possibilities for drug design to block Notum activity in conditions where Wnt is underactive, or alternatively that recombinant Notum could be used as a therapy against excess Wnt signalling in cancer.
The unexpected discovery that Notum deacylates Wnt proteins
1 March 2015
Matthias Zebisch, Yvonne Jones and colleagues in STRUBI, in collaboration with Jean-Paul Vincent's group at the National Institute of Medical Research in Mill Hill, have discovered a unique feedback mechanism that controls an important signalling molecule, Wnt, published in Nature this month.