Trends in Biochemical Sciences
ReviewRegulation of phosphoinositide 3-kinase expression in health and disease
Section snippets
Dynamic regulation of phosphoinositide 3-kinase expression
The importance of the phosphoinositide 3-kinase (PI3K) signalling axis in a wide variety of normal and pathological responses is now well established. Most studies to date have focused on the acute alterations in PI3K activity induced by cell stimulation, and its impact on early downstream signalling by protein effectors of the PI3K lipids. However, emerging evidence indicates that more sustained changes in PI3K gene expression occur under various conditions, leading to persistent alterations
The PI3K family
PI3Ks generate 3-phosphorylated phosphoinositide lipids that transmit intracellular signals by binding to various protein effectors (for a review, see Ref. [1]). Mammals have genes for eight catalytic and six regulatory subunits (Table 1). The PI3Ks have been divided into three classes [1], of which the class I PI3Ks have been studied most extensively and which are the focus of this review. The expression patterns and mode of regulation of class II and III PI3Ks are less well understood (Box 1).
PI3K tissue distribution
Most PI3K subunits seem to have a broad tissue distribution, with p110γ 6, 7 and p110δ 8, 9 being highly enriched in leukocytes (Table 2). At the moment, PI3K expression patterns have only been studied at low resolution using approaches that do not enable discrimination between the different cell types in a tissue. In addition, high quality antibodies to PI3K subunits, especially antibodies that are validated for use in immunohistochemistry, are not available. In the rare instances in which
Dynamic regulation of the ratio of p85 to p110 subunits – a mechanism to regulate PI3K activity?
Under basal conditions, class IA PI3Ks are thought to exist mainly as obligate heterodimers, with the regulatory and catalytic subunits constitutively bound to each other. This model is based on the notion that the p85 and p110 proteins bind each other extremely tightly, an interaction that can withstand high concentrations of salt, urea or detergent 15, 16. Furthermore, both the catalytic [17] and the regulatory subunits 18, 19 seem to be unstable as monomers. Together, this is expected to
Regulation of class I PI3K gene expression
The investigation of molecular mechanisms controlling PI3K gene regulation and expression has only recently been initiated, with promoter analyses for PIK3CA 10, 42, 43 and PIK3CG [44] and the identification of transcription factors that control expression of p110α 10, 42, 43, p55α 45, 46, p50α [45] and p55γ [47] and identification of micro-RNAs that negatively regulate p85α [48] and p85β mRNA levels [49]. Emerging evidence indicates that PI3K expression can be modulated during cell
Concluding remarks
Under basal (i.e. unstimulated) conditions, the expression of the PI3K regulatory and catalytic subunits seems to fall mainly under transcriptional control, with mRNA levels correlating well with protein levels, leading to equal amounts of p85 and p110 protein in cells [20]. Stimuli and transcription factors that induce PI3K gene expression have recently been identified. Some stimuli (such as a CB1 antagonist and estradiol) can induce an immediate, initial increase in PI3K activity owing to
Acknowledgements
We thank Antonio Bilancio, Jan Domin, Emilio Hirsch, Klaus Okkenhaug and members of the Cell Signalling group for critical reading of the manuscript. Personal support was from the Amsterdam Medical Centre and the University of Groningen, The Netherlands (to K.K.), Roche Research Foundation, Switzerland, Janggen-Pöhn Stiftung, Switzerland and Uarda-Frutiger Fonds, Switzerland (to B.G.), and the Ludwig Institute for Cancer Research (to K.K., B.G., B.V.). Work in the B.V. laboratory was supported
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