University of Dundee

Professor Tricia Cohen FRSB

Protein phosphatases in cellular regulation
Position: 
Professor of Molecular Biology
Address: 
Cell Signalling and Immunology, The Sir James Black Centre, University of Dundee, Dundee DD1 5EH
Full Telephone: 
+44 (0) 1382 384240, int ext 84240
Email: 

Research

The Role of Protein Phosphatases in Diabetes and Cancer
 

Diabetes and cancer, which affect millions of people world wide, are among the many disorders that involve alterations cellular regulation. The addition and removal of phosphate from proteins plays a major and essential role in cellular regulation.  For example, glycogen metabolism, cell division and transcription are regulated by protein phosphorylation and dephosphorylation reactions.  In order to understand how phosphate levels in proteins control key cellular events and how they may be altered in disease processes, it is necessary to understand the functions and regulation of the protein kinases that attach phosphate to proteins and the protein phosphatases that remove the phosphate.  Knowledge of these processes may provide potential drug targets for the treatment of the many disorders, like diabetes and cancer, caused by both genetic and environmental factors.

The research of my laboratory investigates the intracellular protein phosphatases that dephosphorylate serine and threonine residues, such as protein phosphatase 1 (PP1), PP4 and PP5.  PP1 is controlled by a great variety of targeting proteins, which confer special properties upon the PP1 catalytic subunit and thus enable it to regulate diverse functions.  Complexes of PP4 that regulate critical cellular events are currently being discovered, while PP5 may regulate multiple functions with a single regulatory region that is attached to the catalytic section. Using a multidisciplinary approach, we are delineating the physiological roles of particular protein phosphatase complexes or protein phosphatase interactions that may regulate signalling pathways critical for human health and therefore encompassing potential drug targets. A major focus of the laboratory is to expand our elucidation of the physiological roles of these protein phosphatases and investigate potential drug targets by variety of techniques including RNA interference in cultured cells and gene targeting in mammals and lower organisms.

Left: The hormone glucagon (or adrenaline) stimulates the breakdown of glycogen in the liver to release glucose into the blood when the blood glucose levels are low.  The process is mediated by an increase in the level of the active (a) form of phosphorylase, which also inhibits glycogen targeted protein phosphate 1 (PP1-GL), thus causing a reciprocal decrease in glycogen synthesis.  In type 2 diabetes glucose levels are high and hepatic glycogen breakdown and glucose output is elevated. A drug which blocks the interaction of phosphorylase a with GL may increase glycogen synthesis and decrease blood glucose levels.
Right: Protein phosphatase 4 regulates many crucial cellular processes by the ability of the catalytic subunit (Ppp4c) to interact with a core regulatory subunit (R1 or R2) and a variable or absent subunit (Rvar).  For example, a Ppp4c-R2-R3 complex participates in resistance to the anticancer drug cisplatin in yeast (see ref. 3).

Past Lab Workers

Cristina Martin Grandos
Doron Rosenzweig
Ian Kelsall
James Paterson
Barry Toole
Cristina Vázquez-Martín
Senga Oxenham
Tamás Zeke
Alasdair Street
Gareth Browne
Neil Brewis
Edgar da Cruz e Silva
Odete Beirao da Cruz e Silva
David Warburton
Norbert Berndt
Viktor Dombrádi
Valerie Hughes
David Mann
David Barford
Anneliese Müller
Maoxiang Chen
Yu Hua Chen
Linda Brown
Christopher Armstrong
Hilary Snaith
Nicholas Helps
Martin Doherty
James Hastie
Emma Borthwick
Xinmei Luo
Graeme Carnegie
Mirela Delibegovic
Shonagh Munro
Amanda Philp
Julie Diplexcito
Martin Voss
Kathryn Campbell
Jacob Wright
Christopher Ford
Max Biegler
Nastja Saranzewa 

Publications

Jacob, W., Rosenzweig, D., Vazquez-Martin, C., Duce, S. L. and Cohen, P. T. (2015) Decreased adipogenesis and adipose tissue in mice with inactivated protein phosphatase 5. The Biochemical journal. 466, 163-176
d.o.i 10.1042/BJ20140428
PMC: 25437352

Voss, M., Campbell, K., Saranzewa, N., Campbell, D. G., Hastie, C. J., Peggie, M. W., Martin-Granados, C., Prescott, A. R. and Cohen, P. T. (2013) Protein phosphatase 4 is phosphorylated and inactivated by Cdk in response to spindle toxins and interacts with gamma-tubulin. Cell cycle. 12, 2876-2887
d.o.i 10.4161/cc.25919
Pubmed: 3899200
PMC: 23966160

Kelsall, I. R., Voss, M., Munro, S., Cuthbertson, D. J. and Cohen, P. T. (2011) R3F, a novel membrane-associated glycogen targeting subunit of protein phosphatase 1 regulates glycogen synthase in astrocytoma cells in response to glucose and extracellular signals. Journal of neurochemistry. 118, 596-610
d.o.i 10.1111/j.1471-4159.2011.07345.x
PMC: 21668450

Voss, M., Paterson, J., Kelsall, I. R., Martin-Granados, C., Hastie, C. J., Peggie, M. W. and Cohen, P. T. (2011) Ppm1E is an in cellulo AMP-activated protein kinase phosphatase. Cellular signalling. 23, 114-124
d.o.i 10.1016/j.cellsig.2010.08.010
PMC: 20801214

Cohen, P. T. W. (2010). Sorting the protein phosphatases: okadaic acid led the way. Available online http://www.biochemj.org/bj/cp/2010/bj2010c001.htm. The Biochemist Classic Article  32, pp. 22-27

Kelsall, I. R., Rosenzweig, D. and Cohen, P. T. (2009) Disruption of the allosteric phosphorylase a regulation of the hepatic glycogen-targeted protein phosphatase 1 improves glucose tolerance in vivo. Cellular signalling. 21, 1123-1134
d.o.i 10.1016/j.cellsig.2009.03.001
PMC: 19275933

Martin-Granados, C., Philp, A., Oxenham, S. K., Prescott, A. R. and Cohen, P. T. (2008) Depletion of protein phosphatase 4 in human cells reveals essential roles in centrosome maturation, cell migration and the regulation of Rho GTPases. The international journal of biochemistry & cell biology. 40, 2315-2332
d.o.i 10.1016/j.biocel.2008.03.021
PMC: 18487071

Kelsall, I. R., Munro, S., Hallyburton, I., Treadway, J. L. and Cohen, P. T. (2007) The hepatic PP1 glycogen-targeting subunit interaction with phosphorylase a can be blocked by C-terminal tyrosine deletion or an indole drug. FEBS letters. 581, 4749-4753
d.o.i 10.1016/j.febslet.2007.08.073
PMC: 17870073

Cohen, P. T., Philp, A. and Vazquez-Martin, C. (2005) Protein phosphatase 4--from obscurity to vital functions. FEBS letters. 579, 3278-3286
d.o.i 10.1016/j.febslet.2005.04.070
PMC: 15913612

Cohen, P. T. (2002) Protein phosphatase 1--targeted in many directions. Journal of cell science. 115, 241-256
PMC: 1183977

Impact

Funding

Diabetes UK

Diabetes UK is the largest organisation in the UK working for people with diabetes, funding research, campaigning and helping people live with the condition.

External link