Novel stem cell protein could unlock new cancer and neurodegenerative disease therapies

Newly-discovered properties of Notum could support pioneering stem-cell medicine

Professor Yvonne Jones, Joint Head of the Division of Structural Biology (STRUBI) in the Nuffield Department of Clinical Medicine at Oxford University
Professor Yvonne Jones, Joint Head of the Division of Structural Biology (STRUBI) in the Nuffield Department of Clinical Medicine at Oxford University
 
Scientists from the University of Oxford have used Diamond to help uncover previously unknown properties of a protein that could have major implications for both neurological and cancer research.
 
The team discovered that the protein, called Notum, indirectly determines the behaviour of stem cells by acting on a ligand called Wnt that sends signals to the cells. Cells communicate with each other by sending out substances like Wnt, which cross over to other cells and pass a message along, thus generating some sort of behaviour in the receptor cell.
 
Wnt has a special lipid ‘finger’ that it uses to hook into its receptor on target cells so that it can pass messages along. The team from Oxford discovered that Notum plays a key part in this process by determining how long Wnt is able to transmit its signal for.  At a certain point, Notum jumps in and cuts off Wnt’s finger, stopping the signalling process.
 
Now that we know how this process works, scientists could develop ways of manipulating the activity of Notum to create more or less signalling between Wnt and stem cells. Being able to control this process has significant medical benefits because of the central role that stem cells play in disease development and therapy, particularly when it comes to cancer and neurological conditions.

 

Strubi banner fig – A multidisciplinary approach ranging from fly genetics to protein crystallography revealed that Notum functions by cutting off Wnt’s ‘finger’ and so switch off its ability to trigger signal
Strubi banner fig – A multidisciplinary approach ranging from fly genetics to protein crystallography revealed that Notum functions by cutting off Wnt’s ‘finger’ and so switch off its ability to trigger signal
Wnt signalling is a vital process for our cells to function, but sometimes it can go wrong. Overactivation of Wnt can lead to cancer, and so the role of Notum is really important. With the opportunity to manipulate the function of Notum now realised, scientists could develop new methods of preventing Wnt overactivation and thus potentially helping to counteract cancer.
 
On the other end of the scale, by inhibiting Notum, it could be possible to allow Wnt to trigger production of more neuronal stem cells. Stem cells have the unique quality of being able to develop into other kinds of biological cell, neuronal stem cells are particularly useful in the treatment of neurological conditions in which the brain has deteriorated in some form. A greater understanding of Notum could be a key that unlocks new research into therapies for these conditions.
 
A slice through the crystal structure of Notum (grey) revealing the large cavity that Notum uses to dock onto the Wnt ‘finger’ (orange).
A slice through the crystal structure of Notum (grey) revealing the large cavity that Notum uses to dock onto the Wnt ‘finger’ (orange).
Professor Yvonne Jones is Joint Head of the Division of Structural Biology (STRUBI) in the Nuffield Department of Clinical Medicine at Oxford University; she headed a team whose work was central to the discovery of Notum’s role. She comments: “It has been tremendously exciting to discover that Notum has this completely unsuspected role, and, using Diamond, to capture atomic level details of it at work.”
 
In a multi-disciplinary collaboration scientists uncovered the significance of Notum through a range of experimental methods. They explored the protein’s behaviour in fruit fly genetics at the MRC NIMR, and studied the structure and function at STRUBI in Oxford. The team from STRUBI collected X-ray data to determine the three dimensional structure of Notum using the macromolecular crystallography (MX) beamlines i02, i03, i04, i04-1 and i24 at Diamond. The research was funded by a range of partners including Cancer Research UK and the Wellcome Trust*.
 
The vital work of these scientists in uncovering the unknown properties of this once overlooked protein is likely to have a real impact on research in the years to come. The newly-discovered properties of Notum and its role in the control of Wnt give it a heretofore unrealised significance in cancer and neurological research, opening the door to new studies and new opportunities for discovery.
 
 
* Funders in full: CRUK, MRC, WT, ERC, UK Research Council Basic Technology Initiative, Marie Curie IEF, Japan Society for the Promotion of Science, University of Oxford Clarendon Fund and Somerville College Scholarships.