BBB seminar: John Ladbury

John Ladbury
University of Leeds, UK

The textbook description of the initiation of a reproducible signal from a receptor tyrosine kinase (RTK) begins with extracellular ligand binding to a receptor followed by the up-regulation of kinase activity leading to phosphorylation of tyrosine residues (pY) to provide binding sites for downstream effector proteins. The signal is transduced by a relay of largely bimolecular binding events which, via a linear pathway, result in a defined and prolonged cellular outcome. In other words the signal transduction process is portrayed as being ‘cranked-up’ from zero to full activity. This simplistic picture is not easy to reconcile in the light of a number of features that emerge from deeper mechanistic studies of receptor signalling.

Here the potential for signalling based on up-regulation of downstream effector proteins through binding of cognate SH3 domains to proline-rich sequences on receptors and the impact of intracellular liquid-liquid phase separation at RTKs will be described. This will provide insight into how RTKs can play a wider role in cellular outputs and response to environmental stressors, as well as highlight novel approaches to drug development and mechanisms of therapeutic resistance.

Chairperson: Jim Lorens, Department of Biomedicine