Life Sciences Research for Lifelong Health

Research

Len Stephens and Phill Hawkins are jointly responsible for a laboratory currently comprising 7 post-docs, 4 PhD students and 1 research technician. 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.

PI3Ks are classified according the nomenclature of their catalytic subunits (p110α, -β, -γ and -δ). p110α, -β, and -δ associate with p85 or p50-p55 regulatory subunits and together they constitute the Class IA PI3Ks.

Class IA PI3Ks are classically activated through protein tyrosine kinase-coupled receptors. Figure 1 shows the activation of Class 1A PI3Ks by protein tyrosine kinase-coupled receptors.
Activation of class 1A PI3Ks

Activation of class 1B PI3Ks

p110γ associates with p101 or p84 regulatory subunits and constitutes the Class IB PI3K.

Class IB PI3K signals downstream of G-protein coupled receptors.

FIgure 2 shows the activation of Class 1B PI3Ks by G-protein coupled 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 (PI(3,4,5)P3) in the inner leaflet of the plasma membrane. 

The PI(3,4,5)P3 that is then made is thought to regulate the location and activity of several primary effectors by binding to conserved domains within their protein structure, the most clearly understood of which are a subgroup of pleckstrin homology (PH) domains. Thus, PI(3,4,5)P3 is thought to co-ordinate the regulation of various downstream responses.

Figure 3 (right) shows that PI(3,4,5)P3 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. Figure adapted from Hawkins et al., 2006.
 
PIP3 is a critical second messenger