Cytokine receptors transmit signals between the extracellular environment and the cell’s internal machinery and cause cells to respond in a variety of ways such as maintenance of viability or proliferation. Abnormalities including enhanced cell viability or survival, and increased cell proliferation are hallmarks of cancer.
Our laboratory seeks to understand the mechanism of cytokine receptor activation, in particular GM-CSF, IL-3 and IL-5 receptors, in health and disease. This will reveal universal biological rules and allow the development of new drugs for diseases such as leukaemia, asthma and arthritis.
Our research program includes structural biology approaches to elucidate the structure and function of these receptors; and functional and proteomics approaches to elucidate the signalling mechanisms and functional consequences of cytokine receptor engagement.
Current research projects
Our projects are utilising cutting edge genetic, molecular and cell biology techniques, proteomics and analyses of signalling pathways.
- Establishing the biological significance of increased IL-3 receptor expression in leukaemia: Having developed an antibody specific to the IL-3 receptor that is currently in clinical trials in leukaemia, we are now seeking to define the biological significance of IL-3 receptor over expression as well as studying the role of this receptor in autoimmunity.
- Dynamic assembly of the human GM-CSF receptor and role in signalling initiation: We have identified the sequential steps required for GM-CSF receptor activation. This project aims to define the roles of each step in terms of protein-protein interacting surfaces and in terms of its functional consequences.
- The human GM-CSF and IL-3 receptor signalling complexes: We have identified specific signalling proteins that bind to the cytoplasmic region of the GM-CSF and IL-3 receptors and we are studying how these proteins contribute to signalosomes. This project aims to define the key mechanism of adaptor protein assembly and its functional role.
- Characterising downstream effectors of sphingosine and determining their role in cancer biology: Cancer cells adopt multiple molecular mechanisms to evade cell death, one of which is the pro-survival 14-3-3 proteins. We have recently identified that the survival function of the 14-3-3 proteins is regulated by sphingosine. We are elucidating the molecular mechanisms involved in this new signalling pathway with the aim of harnessing this process to develop new anti-cancer agents.
Kular, J., K. G. Scheer, N. T. Pyne, A. H. Allam, A. N. Pollard, A. Magenau, R. L. Wright, N. Kolesnikoff, P. A. Moretti, L. Wullkopf, F. C. Stomski, A. J. Cowin, J. M. Woodcock, M. A. Grimbaldeston, S. M. Pitson, P. Timpson, H. S. Ramshaw, A. F. Lopez and M. S. Samuel. "A Negative Regulatory Mechanism Involving 14-3-3 zeta Limits Signaling Downstream of ROCK to Regulate Tissue Stiffness in Epidermal Homeostasis." Developmental Cell 35: 759-774. (2015)
Woodcock, J. M., C. Coolen, K. L. Goodwin, D. J. Baek, R. Bittman, M. S. Samuel, S. M. Pitson and A. F. Lopez. "Destabilisation of dimeric 14-3-3 proteins as a novel approach to anti-cancer therapeutics." Oncotarget 6: 14522-14536. (2015)
Broughton, S. E., T. R. Hercus, M. P. Hardy, B. J. McClure, T. L. Nero, M. Dottore, H. Huynh, H. Braley, E. F. Barry, W. L. Kan, U. Dhagat, P. Scotney, D. Hartman, S. J. Busfield, C. M. Owczarek, A. D. Nash, N. J. Wilson, M. W. Parker and A. F. Lopez. "Dual Mechanism of Interleukin-3 Receptor Blockade by an Anti-Cancer Antibody." Cell Reports 8: 409-418. (2014)
Busfield, S. J., M. Biondo, M. Wong, H. S. Ramshaw, E. M. Lee, S. Ghosh, H. Braley, C. Panousis, A. W. Roberts, S. Z. He, D. Thomas, L. Fabri, G. Vairo, R. B. Lock, A. F. Lopez and A. D. Nash. "Targeting of acute myeloid leukemia in vitro and in vivo with an anti-CD123 mAb engineered for optimal ADCC." Leukemia 28: 2213-2221. (2014)