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Professor Stephen M. Keyse
Head: Cancer Research UK Stress Response Laboratory
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E-mail: s.m.keyse@dundee.ac.uk Tel. 01382 632622
Mammalian cells possess a complex multicomponent machinery that allows them to respond and adapt to environmental stress. Such responses are dependent on a network of signal transduction pathways, which mediate diverse physiological effects including changes in gene expression. These pathways are activated by a wide variety of stress conditions including heat shock, oxidative stress, exposure to genotoxic chemicals and radiation. The physiological outcome of signalling is dependent on both the cell type and the nature and severity of the insult. Cells may either become stress resistant or the insult may result in growth arrest and the elimination of damaged cells by apoptosis. This balance between cell survival and cell death is a critical determinant of cellular sensitivity to both cytotoxic drugs and radiotherapy used in the treatment of human cancers. In addition, many of the components of stress activated signalling pathways are also involved in the process of oncogenic transformation itself. A complete understanding of the functions and interaction of these pathways is of fundamental importance and will reveal important new targets and approaches for the treatment of human disease.
MAP kinase cascades are key components of the signalling networks that sense cellular exposure to environmental stress. So far 13 MAP kinases have been identified in mammalian cells. These include the ERK1/ERK2 MAP kinase cascade, which is activated by a variety of hormones and growth factors. A second group of MAP kinases are strongly activated by cellular stress. This group includes the c-Jun amino terminal kinases (JNKs) and p38 MAP kinase isoforms. The balance of signalling through these distinct MAP kinase cascades is thought to be important in determining the cellular response in terms of either cell survival or apoptosis.
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It is now clear that the duration and magnitude of signalling through MAP kinase pathways is a critical determinant of biological effect. All MAP kinases are activated by phosphorylation of both threonine and tyrosine residues within the conserved signature sequence T-X-Y by a dual specificity MAP kinase kinase (MEK or MKK). A balance between the activity of this enzyme and specific protein phosphatases is likely to be a critical determinant of MAP kinase activity.
In recent years we have been involved in the isolation and characterisation of dual-specificity (Thr/Tyr) MAP kinase phosphatases (MKPs) in mammalian cells. Ten such genes have thus far been identified and a subset of these are regulated at the transcriptional level in response to many of the stimuli which activate MAP kinase signalling. This indicates that they act as negative feedback regulators of MAP kinase activity. In addition, these enzymes exhibit substrate selectivity towards different MAP kinase isoforms and are differentially localised within cells. Current work in our laboratory is focused on the characterisation of these enzymes and the determination of their roles in modulating the physiological outcome of MAP kinase activity in cells and tissues under both normal and pathological conditions such as cancer.
Work in my laboratory is supported by Cancer Research UK.
References
Keyse, S.M. and Emslie, E.A. (1992) Oxidative stress and heat shock induce a human gene encoding a protein-tyrosine phosphatase. Nature 359:644-646.
Groom, L.A., Sneddon, A.A, Alessi, D.R., Dowd, S. and Keyse S.M. (1996) Differential regulation of the MAP and SAP kinases by Pyst1, a novel cytosolic dual specificity phosphatase. EMBO J. 15: 3621-3622.
Stewart, A.E., Dowd, S., Keyse, S.M. and McDonald, N.Q. (1999) Crystal structure of the MAPK phosphatase Pyst1 catalytic domain and implications for regulated activation. Nature Structural Biology 6: 174-181.
Keyse, S.M.(2000) Protein phosphatases and the regulation of mitogen-activated protein kinase signalling. Curr. Opin. Cell Biol. 12: 186-192.
Slack, D.N., Seternes, O-M., Gabrielsen, M. and Keyse S.M. (2001) Distinct binding determinants for ERK2/p38? and JNK MAP Kinases mediate catalytic activation and substrate selectivity of MAP Kinase Phosphatase-1. J. Biol. Chem. 276: 16491-16500.
Eblaghie, M.C., Lunn, S.J., Dickinson, R.J., Munsterberg, A.E., Sanz-Ezquerro, J.-J., Farrell, E.R., Mathers, J., Keyse, S.M. Storey, K. and Tickle, C. (2003) Negative feedback regulation of FGF signalling levels by Pyst1/MKP3 in chick embryos. Current. Biol. 13: 1009-1018.
Karlsson, M., Mathers, J., Dickinson, R.J., Mandl, M. and Keyse, S.M. (2004) Both nuclear-cytoplasmic shuttling of the dual-specificity phosphatase MKP-3 and its ability to anchor MAP kinase in the cytoplasm are mediated by a conserved nuclear export signal. J. Biol. Chem. 279: 41882-41891.
Seternes, O.-M., Mikalsen, T., Johansen, B., Michaelsen, E., Armstrong, C.G., Morrice, N.A., Turgeon, B., Meloche, S., Moens, U and Keyse, S.M. (2004) Activation of MK5/PRAK by the atypical MAP kinase ERK3 defines a novel signal transduction pathway. EMBO J. 23, 4780-4791.
Mandl, M., Slack, D.N. and Keyse, S.M. (2005) Specific inactivation and nuclear anchoring of ERK2 MAP kinase by the inducible dual-specificity protein phosphatase DUSP5. Mol. Cell. Biol. 25: 1830-1845.
Christie, G.R., Williams, D.J., MacIsaac, F., Dickinson, R.J., Rosewell, I. and Keyse, S.M., (2005) The dual-specificity protein phosphatase DUSP9/MKP-4 is essential for placental function but is not required for normal embryonic development. Mol. Cell. Biol. 25:8323-8333.
Dickinson, R.J. and Keyse, S.M. (2006) Diverse physiological finctions for dual-specificity MAP kinase phosphatases. J. Cell Sci. 119: 4607-4615
Fox, G.C, Shafiq, M., Briggs, D.C., Knowles, P.P., Collister, M., Didmon, M.J., Makrantoni, V., Dickinson, R.J., Hanrahan, S., Totty, N., Stark, M.J., Keyse, S.M., McDonald, N.Q. (2007) Redox-mediated substrate recognition by Sdp1 defines a new group of tyrosine phosphatases. Nature, May 2007
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