The Laboratory of Molecular Signalling

Cells respond to extracellular cues by generating signals at the plasma membrane (see also Inositide Laboratory). These signals are transduced through the cytoplasm to intracellular organelles such as the nucleus, ER and mitochondria to influence gene expression, cellular metabolism and cell fate decisions such as growth, proliferation, differentiation and death. We are studying two ubiquitous, highly conserved and interrelated signalling mechanisms: the mobilization of intracellular calcium stores and the activation of the Akt and MAPK protein kinase signalling cascades.

We are seeking to understand how these signal pathways function and are regulated in time and space and how they act to influence cell fate decisions through the regulation of short term non-genomic targets and long term genomic targets. This includes the identification of new targets or effectors of these pathways (proteomics and genomics) that are responsible for influencing gene expression and/or organelle function.

These pathways underpin normal development and homeostasis and may be de-regulated in normal age-related disorders. In addition, they are certainly de-regulated in a variety of human diseases including cardiac arrhythmias, auto-immunity, inflammation, neurodegenerative conditions and cancer, making them attractive drug targets. Indeed, research in this area is bringing new understanding of a wide range of medical disorders and with it the potential to develop ever more sophisticated therapeutic strategies for the prevention and management of disease.


Specific research areas include:-

1. The role of calcium as a universal signal in cell regulation. The elementary events resulting from the opening of inositol trisphosphate or ryanodine receptors are studied using high-resolution confocal microscopy and the versatility of this signalling mechanism is being explored in neuronal and cardiac cells. The role of calcium in regulating the activation of Ras-related GTPases is also under investigation and provides links with the MAPK pathways (below) and with other colleagues studying GTPases in the immune system.

2. The mitogen-activated protein kinase (MAPK) super-family and PI3 kinase/Akt group of enzymes. In common with calcium, these protein kinase signalling pathways regulate cell fate decisions such as cell cycle progression and apoptosis, and are being studied in cultured fibroblasts, tumour cells and differentiating myoblasts.

3. Activation of calcium fluxes and MAPKs are common responses to fertilisation but there is also an interest in events prior to fertilisation that include the identification and organisation of molecules within the plasma membrane of spermatozoa that mediate specific binding to receptors on the zona pellucida of the egg.

4. Molecular signalling events that regulate the degeneration of axons in injury and neurodegenerative disease. Intracellular calcium release, MAPK signalling pathways, and the signalling roles of NAD are being studied to understand how they may contribute to the neuroprotective action of the slow Wallerian degeneration protein, WldS.

• Key publications from the laboratory
• Translating the Laboratory's Research into Action