4 South 0.42
Tel: +44 (0) 1225 383346
- BSc University of Bristol (1994 - 1997)
- PhD University of Sheffield (1999 - 2002)
- Post-doctoral work University of Bristol (2002 - 2010)
- Lecturer in Cell Biology University of Bath (2010 - present)
Chris Bryant (PhD student, co-supervised by Andy Chalmers and Paul Whitley).
Dr Christopher Caunt
(known as Jim Caunt)
Our research focuses on mechanisms of receptor signalling through mitogen-activated protein kinase (MAPK) cascades, which control the four basic decisions cells can make: whether to survive, replicate, differentiate or die. Our work is concentrated on the prototypic Raf-MEK-ERK (extracellular signal regulated kinase) pathway, which serves to relay signals from growth factor, integrin and hormone receptors to the cell interior. Appropriate regulation of the ERK cascade is essential for normal embryonic development, and it is deregulated with alarming frequency in human tumours, making ERK pathway components critical drug targets for controlling tumourigenesis.
Our work is therefore focused on two central questions:
- Many stimuli activate ERK, so how are specific biological responses generated?
- With a ubiquitous and essential role in all cells, how can we target ERK in disease with specificity?
It is now clear that both the kinetics and compartmentalisation of ERK responses govern the specificity of cell signalling and the biological outcome. These “spatiotemporal” characteristics are in turn governed by a series of distinct biochemical motifs. Chief among these is phosphorylation of a Thr-Glu-Tyr (TEY) motif, which both activates ERK and causes its release from cytosolic anchors, allowing it to accumulate in the nucleus and phosphorylate key transcriptional targets. Three additional phosphorylation sites and several spatially distinct interaction domains may also contribute to ERK regulation but how these influence ERK movement, activation and substrate targeting is currently unclear. We use a number of cell biology techniques (such as siRNA transfection, adenovirus manufacture and transduction, site-directed mutagenesis, confocal microscopy, high-content microscopy, immunoprecipitation and western blotting) to study how ERK and its binding partners control cell behaviour. Our recent findings indicate a major role for a number of dual-specificity phosphatase (DUSP) proteins in the control of both ERK activity and localisation, and are currently a major focus of our research.
Kidger, A. M., Rushworth, L. K., Stellzig, J., Davidson, J., Bryant, C. J., Bayley, C., Caddye, E., Rogers, T., Keyse, S. M. and Caunt, C. J., 2017. Dual-specificity phosphatase 5 controls the localized inhibition, propagation, and transforming potential of ERK signaling. Proceedings of the National Academy of Sciences of the United States of America, 114 (3), E317-E326.
Dayalan Naidu, S., Sutherland, C., Zhang, Y., Risco, A., de la Vega, L., Caunt, C. J., Hastie, C. J., Lamont, D. J., Torrente, L., Chowdhry, S., Benjamin, I. J., Keyse, S. M., Cuenda, A. and Dinkova-Kostova, A. T., 2016. Heat shock factor 1 is a substrate for p38 mitogen-activated Protein Kinases. Molecular and Cellular Biology, 36 (18), pp. 2403-2417.
Caunt, C. J., Kidger, A. M. and Keyse, S. M., 2016. Visualizing and quantitating the spatiotemporal regulation of Ras/ERK signaling by dual-specificity mitogen-activated protein phosphatases (MKPs). In: Pulido, R., ed. Protein Tyrosine Phosphatases. Springer, pp. 197-215.
Garner, K. L., Perrett, R. M., Voliotis, M., Bowsher, C., Pope, G. R., Pham, T., Caunt, C. J., Tsaneva-Atanasova, K. and McArdle, C. A., 2016. Information transfer in gonadotropin-releasing hormone (GnRH) signaling:extracellular signal-regulated kinase (ERK)-mediated feedback loops control hormone sensing. Journal of Biological Chemistry, 291 (5), pp. 2246-2259.
Caunt, C. J., Sale, M. J., Smith, P. D. and Cook, S. J., 2015. MEK1 and MEK2 inhibitors and cancer therapy:the long and winding road. Nature Reviews Cancer, 15 (10), 577–592.
Rushworth, L. K., Kidger, A. M., Delavaine, L., Stewart, G., Van Schelven, S., Davidson, J., Bryant, C. J., Caddye, E., East, P., Caunt, C. J. and Keyse, S. M., 2014. Dual-specificity phosphatase 5 regulates nuclear ERK activity and suppresses skin cancer by inhibiting mutant Harvey-Ras (HRas Q61L)-driven SerpinB2 expression. Proceedings of the National Academy of Sciences of the United States of America, 111 (51), pp. 18267-18272.
Bryant, C. J., Keyse, S. M. and Caunt, C. J., 2014. BRAF inhibitor resistance:are holidays and cocktails the answer? Pigment Cell & Melanoma Research, 27 (5), pp. 693-695.
Helsby, M. A., Leader, P. M., Fenn, J. R., Gulsen, T., Bryant, C., Doughton, G., Sharpe, B., Whitley, P., Caunt, C. J., James, K., Pope, A. D., Kelly, D. H. and Chalmers, A. D., 2014. CiteAb:A searchable antibody database that ranks antibodies by the number of times they have been cited. BMC Cell Biology, 15 (1), 6.
Perrett, R.M., Fowkes, R.C., Caunt, C.J., Tsaneva-Atanasova, K., Bowsher, C.G. and McArdle, C.A., 2013. Signaling to extracellular signal-regulated kinase from ErbB1 kinase and protein kinase c:Feedback, heterogeneity, and gating. Journal of Biological Chemistry, 288 (29), pp. 21001-21014.
Pereira Morais, M. P., Marshall, D., Flower, S. E., Caunt, C. J., James, T. D., Williams, R. J., Waterfield, N. R. and Van Den Elsen, J. M. H., 2013. Analysis of protein glycation using fluorescent phenylboronate gel electrophoresis. Scientific Reports, 3, 1437.
Caunt, J. and Keyse, S. M., 2013. Dual-specificity MAP kinase phosphatases (MKPs):Shaping the outcome of MAP kinase signalling. FEBS Journal, 280 (2), pp. 489-504.
Finch, A. R., Caunt, C. J., Perrett, R. M., Tsaneva-Atanasova, K. and McArdle, C. A., 2012. Dual specificity phosphatases 10 and 16 are positive regulators of EGF-stimulated ERK activity: Indirect regulation of ERK signals by JNK/p38 selective MAPK phosphatases. Cellular Signalling, 24 (5), pp. 1002-1011.
Tsaneva-Atanasova, K., Mina, P., Caunt, C. J., Armstrong, S. P. and McArdle, C. A., 2012. Decoding GnRH neurohormone pulse frequency by convergent signalling modules. Journal of the Royal Society, Interface, 9 (66), pp. 170-182.
Caunt, C. J. and McArdle, C. A., 2012. ERK phosphorylation and nuclear accumulation: Insights from single-cell imaging. Biochemical Society Transactions, 40 (1), pp. 224-229.
Caunt, C.J., Perett, R.M., Fowkes, R.C. and McArdle, C.A., 2012. Mechanisms of GnRH-induced extracellular signal-regulated kinase nuclear localization. PLoS ONE, 7 (7), e40077.
Dukes, J. D., Fish, L., Richardson, J. D., Blaikley, E., Burns, S., Caunt, C. J., Chalmers, A. D. and Whitley, P., 2011. Functional ESCRT machinery is required for constitutive recycling of claudin-1 and maintenance of polarity in vertebrate epithelial cells. Molecular Biology of the Cell, 22 (17), pp. 3192-3205.
Armstrong, S. P., Caunt, C. J., Finch, A. R. and McArdle, C. A., 2011. Using automated imaging to interrogate gonadotrophin-releasing hormone receptor trafficking and function. Molecular and Cellular Endocrinology, 331 (2), pp. 194-204.
Caunt, C. J. and McArdle, C. A., 2010. Stimulus-induced uncoupling of extracellular signal-regulated kinase phosphorylation from nuclear localization is dependent on docking domain interactions. Journal of Cell Science, 123 (24), pp. 4310-4320.
Welsh, G. I., Hale, L. J., Eremina, V., Jeansson, M., Maezawa, Y., Lennon, R., Pons, D. A., Owen, R. J., Satchell, S. C., Miles, M. J., Caunt, C. J., McArdle, C. A., Pavenstädt, H., Tavaré, J. M., Herzenberg, A. M., Kahn, C. R., Mathieson, P. W., Quaggin, S. E., Saleem, M. A. and Coward, R. J. M., 2010. Insulin signaling to the glomerular podocyte is critical for normal kidney function. Cell Metabolism, 12 (4), pp. 329-340.
Armstrong, S. P., Caunt, C. J., Fowkes, R. C., Tsaneva-Atanasova, K. and McArdle, C. A., 2010. Pulsatile and sustained Gonadotropin-releasing Hormone (GnRH) receptor signaling: Does the ERK signaling pathway decode GnRH pulse frequencey? Journal of Biological Chemistry, 285 (32), pp. 24360-24371.
Finch, A. R., Sedgley, K. R., Armstrong, S. P., Caunt, C. J. and McArdle, C. A., 2010. Trafficking and signalling of gonadotrophin-releasing hormone receptors:an automated imaging approach. British Journal of Pharmacology, 159 (4), pp. 751-760.
Finch, A. R., Caunt, C. J., Armstrong, S. P. and McArdle, C. A., 2010. Plasma membrane expression of Gonadotropin-Releasing Hormone receptors: regulation by peptide and nonpeptide antagonists. Molecular Endocrinology, 24 (2), pp. 423-435.
Caunt, C. J., Armstrong, S. P. and McArdle, C. A., 2010. Using high-content microscopy to study gonadotrophin-releasing hormone regulation of ERK. Methods in Molecular Biology, 661 (6), pp. 507-524.
Bailey, C. P., Oldfield, S., Llorente, J., Caunt, C. J., Teschemacher, A., Roberts, L., McArdle, C., Smith, F., Dewey, W., Kelly, E. and Henderson, G., 2009. Involvement of PKCα and G-protein-coupled receptor kinase 2 in agonist-selective desensitization of µ-opioid receptors in mature brain neurons. British Journal of Pharmacology, 158 (1), pp. 157-164.
Maru, B., Tobias, J., Rivers, C., Caunt, C., Norman, M. and McArdle, C., 2009. Potential use of an estrogen–glucocorticoid receptor chimera as a drug screen for tissue selective estrogenic activity. Bone, 44 (1), pp. 102-112.
Finch, A. R., Caunt, C. J., Armstrong, S. P. and McArdle, C. A., 2009. Agonist-induced internalization and downregulation of gonadotropin-releasing hormone receptors. American Journal of Physiology - Cell Physiology, 297 (3), C591-C600.
Armstrong, S. P., Caunt, C. J. and McArdle, C. A., 2009. Gonadotropin-Releasing Hormone and protein kinase C signaling to ERK: spatiotemporal regulation of ERK by docking domains and dual-specificity phosphatases. Molecular Endocrinology, 23 (4), pp. 510-519.
Armstrong, S. P., Caunt, C. J., Fowkes, R. C., Tsaneva-Atanasova, K. and McArdle, C. A., 2009. Pulsatile and Sustained Gonadotropin-releasing Hormone (GnRH) Receptor Signaling: does the Ca2+/NFAT signaling pathway decode GnRH pulse frequency? Journal of Biological Chemistry, 284 (51), pp. 35746-35757.
Caunt, C. J., Armstrong, S. P., Rivers, C. A., Norman, M. R. and McArdle, C. A., 2008. Spatiotemporal regulation of ERK2 by dual specificity phosphatases. Journal of Biological Chemistry, 283 (39), pp. 26612-26623.
Caunt, C. J., Rivers, C. A., Conway-Campbell, B. L., Norman, M. R. and McArdle, C. A., 2008. Epidermal growth factor receptor and protein kinase C signaling to ERK2: spatiotemporal regulation of ERK2 by dual specificity phosphatases. Journal of Biological Chemistry, 283 (10), pp. 6241-6252.
Finch, A. R., Sedgley, K. R., Caunt, C. J. and McArdle, C. A., 2008. Plasma membrane expression of GnRH receptors: regulation by antagonists in breast, prostate, and gonadotrope cell lines. The Journal of Endocrinology, 196 (2), pp. 353-367.