The phosphoinositide (PI) 3-kinase family

doi:10.1242/jcs.00609 Phosphoinositide (PI) 3-kinase was first observed in 1984 as a minor inositol lipid kinase activity associated with immunoprecipitated oncogene products (e.g. Src, Abl and polyoma mT antigen) and present in activated growth factor receptor complexes (e.g. PDGF receptor). In 1988, the enzyme associated with this activity was found to have the novel ability to phosphorylate the 3 position hydroxyl group of the inositol ring (see poster) of phosphatidylinositol (PtdIns). PI 3-kinase activities have been subsequently found in all eukaryotic cell types examined (Fry, 1994; Katso et al., 2001) and are linked to an incredibly diverse set of key cellular functions, including cell growth, proliferation, motility, differentiation, survival and intracellular trafficking (Fry, 1994; Rameh and Cantley, 1999; Fry, 2001; Katso et al., 2001). The emerging links between PI 3-kinase activity and many human maladies, including allergy, inflammation, heart disease and cancer, has made them the focus of intense study, and inhibitors of these enzymes are considered potential therapeutic agents (Stein and Waterfield, 2000). Although the majority of published studies have focused on the classical p110-p85 (now known as class I) PI 3-kinases, it has emerged over the past 10 years that the PI 3-kinase superfamily (EC 2.7.1.137) is made up of a large family of structurally related enzymes, with differing PI substrate requirements and modes of regulation, which probably accounts for the reported diversity of function (Rameh and Cantley, 1999; Fry, 2001; Katso et al., 2001). PCR cloning strategies and data mining of genome sequencing projects would seem to set the family limit at eight distinct PI 3-kinase catalytic subunits that are capable of phosphorylating inositol lipids. These eight isoforms have been divided into three functional classes on the basis o