Signalling networks which involve phosphoinositide 3OH-kinases (PI3Ks)

The programmes of work in the laboratory are currently aimed at understanding the molecular mechanisms and physiological significance of intracellular signalling networks which involve phosphoinositide 3OH-kinases (PI3Ks).

PI3Ks are now accepted to be critical regulators of numerous important and complex cell responses, including cell growth, division, survival and movement. PI3Ks catalyse the formation of one or more critical phospholipid messenger molecules, which signal information by binding to specific domains in target proteins. Currently the best understood pathway involves the activation of Class I PI3Ks by cell surface receptors.

It is now known that a huge variety of receptors (e.g. including those for growth factors, antigens and various inflammatory stimuli) from different structural families and with differing signal transduction mechanisms, can activate Class I PI3Ks to synthesise the messenger phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the inner leaflet of the plasma membrane. PIP3 is a critical second messenger that is able to interact with the PH domains of a variety of different proteins. Recruitment and activation of these proteins enables the signal to be relayed to downstream targets, ultimately resulting in regulation of vital cellular functions.

In recent years, the lab has increasingly focused on the role of PI3Ks in the signalling mechanisms which allow cell surface receptors on mammalian neutrophils to control various aspects of neutrophil function. Neutrophils are key players in the front line of our immune system, responsible primarily for the recognition and destruction of bacterial and fungal pathogens. However, they are also involved in the amplification cascades that underlie various inflammatory pathologies, e.g. Acute Respiratory Distress Syndrome (ARDS) and rheumatoid arthritis.