Endocrine Abstracts

Phosphoinositide 3-kinase (PI3K) signalling pathways are now accepted to be widely important in the mechanisms by which a variety of cell surface receptors can regulate critical cellular functions, such as cell growth, survival and movement. Class I PI3Ks generate the messenger lipids PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ in the inner leaflet of the plasma membrane. These two lipids then co-ordinate the regulation of multiple protein targets by binding, with high specificity and affinity, to conserved protein domains, the best characterised of which are a subgroup of pleckstrin-homology (PH) domains. This binding of PtdIns(3,4,5)P₃/PtdIns(3,4)P₂ to PH domain-containing proteins can influence the localisation and function of them e.g. plasma membrane translocation and activation of protein kinases, such as AKT/PKB, or the activation of GEFs and GAPs for small GTPases, such as the cytohesins or ARAPs. The large number of these PH-domain containing effectors, even within a single cell, means the synthesis of PtdIns(3,4,5)P₃ and PtdIns(3,4)P₂ carries a profound regulatory input into multiple cellular pathways. It is now clear that Class I PI3Ks have a particularly important role in growth factor regulation of cell growth, division and survival and indeed mutations in PI3Ks, their upstream regulators and their downstream targets, are thought to be the most common examples of mutations causing human cancers. Class I PI3Ks also play important roles in a diverse range of other pathways and cellular contexts e.g., in response to antigens, neurotransmitters and many different hormones and inflammatory stimuli, in a wide variety of target cells. This widespread importance, combined with their isoform complexity, which can deliver tissue and receptor-specific signalling, has made them attractive drug targets for novel therapeutics, particularly in cancer and inflammation.