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REVIEW

Mutations in Phosphoinositide Metabolizing Enzymes and Human Disease

Heather J. McCrea and Pietro De Camilli

Howard Hughes Medical Institute, Departments of Cell Biology and Neurobiology, Kavli Institute for Neuroscience, Program in Cellular Neuroscience, Neurodegeneration and Repair, Yale University School of Medicine, New Haven, Connecticut pietro.decamilli{at}yale.edu

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.

View larger version (31K): [in this window] [in a new window]   FIGURE 1. Phosphoinositide metabolism and associated disease A: chemical structure of phosphatidylinositol with numbered positions of the inositol ring indicated. B: depiction of the main pathways of phosphoinositide synthesis and degradation. Diseases associated with the kinases and phosphatases that regulate this interconversion are indicated.