1 Nature immunology 2003 Vol: 4(4):313-319. DOI: 10.1038/ni0403-313

The role of PI3K in immune cells.

Members of the phosphoinositide-3 kinase (PI3K) family control several cellular responses including cell growth, survival, cytoskeletal remodeling and the trafficking of intracellular organelles in many different types of cell. In particular PI3K has important functions in the immune system. It has been difficult to evaluate the roles of distinct PI3Ks in cellular immune responses because no PI3K inhibitors are specific for individual family members and because most stimuli activate several PI3K enzymes. The development of gene-targeted mice now enables us to examine the physiological functions of individual PI3K enzymes in the immune system in vivo.

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Figures
Figure 1: Metabolism and immune system functions of phosphoinositides.Phosphorylation of the 4- and 5-position of the inositol ring is catalyzed by distinct phosphoinositide kinases. There are also several 3-, 4- and 5-phosphatases. Kinases and phosphatases that are not discussed in the text are shown in parentheses. DAG, diacylglycerol; IP3, inositol(1,4,5)trisphosphate. Figure 2: Structural characteristics of the PI3K family.The PIK domain is a helical domain that is found in lipid kinases but not protein kinases. C2 domains bind phospholipid in a calcium-dependent and -independent manner; those of PI3Ks do so in a calcium-independent fashion and may recruit PI3Ks to the membrane. The inter-SH2 domain of p85, p55, p50, p85 and p55 constitutively interacts with the N-terminal domain of p110,,. Dual SH2 domains bind to tyrosine-phosphorylated adaptor proteins, leading to activation of the kinase activity of the p110 subunits. p101 specifically interacts with the N-terminal domain of 110. PX domains are known to bind PI(3)P and PI(3,4)P2 and may recruit the class IIPI3K to the membrane. Functions of the Ras-binding domain (Ras-B), SH3 and Bcr domains and the proline-rich region (Pr) are not fully understood. Vps34p, the class III PI3K, forms a complex with a serine/threonine kinase, Vps15p. Figure 3: Signal transduction pathways involving PI3Ks in immune cells.Proteins containing PH domains (PKB, PDK1, Vav and PLC-) are present downstream of PI(3,4)P2 and PI(3,4,5)P3. Various target proteins function downstream of these molecules. For example, p70S6K is involved in cellular proliferation. Proteins containing FYVE and PX domains such as p40phox, function upon binding to PI(3)P and/or PI(3,4)P2. Activation mechanisms of class II and class III PI3Ks are largely unknown.
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