Phosphorylation and Ubiquitylation
Phosphorylation and Ubiquitylation

Almost all aspects of biology are regulated by reversible protein phosphorylation and ubiquitylation. Abnormalities in these pathways cause numerous diseases including cancer, neurodegeneration and inflammation - all conditions under intense scrutiny in our Unit. Deciphering how disruptions in phosphorylation and ubiquitin networks lead to disease will reveal novel drug targets and improved strategies to treat these maladies in the future.

Protein ubiquitylation is analogous to protein phosphorylation except that ubiquitin molecules are attached covalently to Lys residues, as opposed to phosphate groups becoming covalently attached to one or more Ser, Thr or Tyr residues. Like phosphorylation, ubiquitylation can alter protein properties and functions in every conceivable way. Ubiquitylation is likely to be a more versatile control mechanism than phosphorylation, as ubiquitin molecules can not only be linked to one or more amino acid residues on the same protein, but can also form ubiquitin chains. Moreover, there are also several ubiquitin-like modifiers (ULMs), such as Nedd8, SUMO1, SUMO2, SUMO3, FAT10 and ISG15, which can become attached to proteins in reactions termed Neddylation, SUMOylation, Tenylation and ISGylation, while poly-SUMO chains (involving SUMO2 and SUMO3) are also formed in cells. Recent research has highlighted an exquisite interplay between phosphorylation and ubiquitin pathways that regulate many physiological systems. This includes pathways of relevance to understanding innate immunity, Parkinson's disease and cancer, emphasising the importance of integrating phosphorylation and ubiquitylation research, and not considering these separate areas to be studied in isolation.

Phosphorylation Ubiquitylation
Discovered 1955 Discovered 1978
>500 protein kinases ~10 E1s, ~40 E2s
>600 E3 ligases
140 protein phosphatases ~100 deubiquitylases
Nobel Prize 1992

Nobel Prize 2004
First drug approval
2001 (Gleevec)
First drug approval
2003 (Bortezomib)
16 drugs approved,
>150 in clinical trials
15 drugs in Phase I/II
Current sales of
USS$15 billion p.a.
Current sales of
USS$1.5 billion p.a.
30% of Pharma R&D <<1% of Pharma R&D
Protein ubiquitylation is an even more versatile control mechanism
than protein phosphorylation
History of the development of protein phosphorylation and ubiquitylation

 

The MRC-PPU research focuses on unravelling the roles of protein phosphorylation and ubiquitylation pathways that have strong links to understanding human disease. This is where we can make the best use of our expertise, grasp opportunities emerging from the golden era of genetic analysis of human disease, and make a significant contribution to medical research. Our Principal Investigators (PIs) deploy a blend of creativity, curiosity, expertise and state-of-the-art technology to tackle their selected projects. Their aim is to uncover fundamentally new knowledge on how biological systems are controlled, hopefully shedding novel insights into the understanding and treatment of disease. Effective translation of our research will also be impossible without robust interactions with drug discovery units such as the MRC Technology Centre for Therapeutics Discovery, the University of Dundee's Drug Discovery Unit and close collaboration with pharmaceutical companies. The latter will be greatly enhanced by major collaborations with the six pharmaceutical companies that support the Division of Signal Transduction Therapy. Access to the exceptional support services available within the MRC-PPU and DSTT also helps to maximise the competitiveness of our research groups and reinforce collaborations with our external partners.

Central questions being addressed by our PIs include understanding how ubiquitin and phosphorylation pathways are organised, characterising the interplay between these pathways, determining how they recognise and respond to signals, and uncovering how disruption of these networks causes disease. The expectation is that the data, reagents and expertise emerging from our research and working effectively with clinicians and pharmaceutical industry will enable us to devise new strategies to better treat disease.