Email: j.e.ladbury@leeds.ac.uk

Research profile and key clinical specialties

Our research focuses on the pathogenic outcomes from aberrant signalling which is initiated at receptor tyrosine kinases (RTKs).

Most recently, we have focused on the previously under investigated recruitment and activation of proteins via binding toproline-rich binding sites on the receptors. These interactions can occur in the absence of receptor stimulation or up-regulation through genetic mutation.

Thus these interactions occur in conditions which are experienced by cells in normal tissue. As a result a potentially unexplored landscape of signal transduction which occurs in the absence of exposing cells to high concentrations of growth factors exists.

The majority of RTKs have proline-rich motifs which provide sites for downstream effector molecules. For example, phospholipase Cγ1 binds to FGFR2 through its SH3 domain resulting in activation leading to increase metastatic and proliferative potential of cells.

We are screening other RTK proline-rich motifs for binding to downstream effector molecules and exploring novel routes to oncogenesis based on protein concentration fluctuations rather than genetic mutation, i.e. cancer of non-genetic origin.

Two key publications

• Timsah, Z., et al., & Ladbury, J. E. (2016) Grb2 depletion under non-stimulated conditions inhibits PTEN, promotes Akt-induced tumor formation and contributes to poor prognosis in ovarian cancer. Oncogene 35, 2186-2196, doi:10.1038/onc.2015.279
• Timsah, Z., Ahmed, Z., Lin, C. –C., Melo, F. A., Stagg, L. J., Leonard, P. G., Jeyabal, P., Berrout, J., O.Neil, R. G., Bogdanov, M. & Ladbury, J. E. (2014) Competition between Grb2 and Plcγ1 for binding to FGFR2 regulates constitutive phospholipase activity and invasive response. Nature Structural and Molecular Biology 21, 180-188, doi:10.1038/nsmb.2752.

Possible PhD projects

Exploration of the molecular mechanisms associated with pre-cancerous cells from Barrett’s oesophagus using organoid models

More information

I’m currently supervising a PhD student on the Wellcome Trust N4 PhD Programme entitled ‘Determining novel receptor signalling pathways in T cells in health and cancer’.

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Keywords: Barrett’s oesophagus, oeGrb2, pre-cancerous cells, depletion, tyrosine kinases, RTKs, toproline, proteins, phospholipase Cγ1, FGFR2, proline, oncogenesis, genetic mutation, John, Ladbury, Leeds

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