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Phosphoinositides are implicated in the regulation of a wide variety of cellular functions. Their importance in cellular and organismal physiology is underscored by the growing number of human diseases linked to perturbation of kinases and phosphatases that catalyze interconversion from one phosphoinositide to another. Many such enzymes are attractive targets for therapeutic interventions. Here, we review diseases linked to inheritable or somatic mutations of these enzymes. Phosphatidylinositol (PtdIns), a membrane phospholipid, can be reversibly phosphorylated at the 3, 4, and 5 positions of the inositol ring to generate seven phosphoinositides [PI3P, PI4P, PI5P, PI(3,4)P2, PI(4,5)P2, PI(3,5)P2, and PI(3,4,5)P3] (FIGURE 1A). The importance of this metabolism in cell regulation was first established in the context of studies on stimulus-secretion coupling. It was found that many stimuli that trigger secretion also trigger enhanced turnover of PtdIns and phosphoinositides (42). Subsequently, it became clear that phospholipase C-dependent hydrolysis of PI(4,5)P2 to generate the second messenger molecules diacyl glycerol and Ins(1,4,5)P3 (IP3) is a mechanism through which many cell surface receptors, including many receptors that stimulate secretion, transduce their signals (10). Diacyl glycerol binds and regulates protein kinase C and a variety of other effectors, whereas IP3 triggers calcium release from the endoplasmic reticulum (10, 42). In another signal transduction pathway, PI(4,5)P2 is cleaved by phospholipase A2 to generate arachidonic acid, a precursor of many signaling molecules.
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