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• W2087676876 abstract "In the introduction to “A Thematic Series on Phospholipases” that appeared about two years ago (Prescott, S.M. (1997) J. Biol. Chem. 272,15043) I commented that phospholipids are a reservoir for lipid mediators that support many intracellular events and that the initial step leading to their synthesis was activation of a phospholipase. This series reviews another molecular route to generating, and then shutting off, lipid-based signals: phosphorylation (or dephosphorylation) of a lipid. This is a well characterized mechanism for regulating the function of proteins, and the last decade has seen an explosion of information about similar processes in regulating lipid messengers. The first clue was the observation that phosphatidylinositol and its analogs with phosphates on the inositol ring were substrates for the addition of another phosphate and that this reaction occurred at the 3-position of inositol, a previously unrecognized target. This finding led to remarkable insights into signals that regulate cellular growth and differentiation. This important body of work is covered in the first paper, “The Role of Phosphoinositide 3-Kinase Lipid Products in Cell Function” by Lucia E. Rameh and Lewis C. Cantley. The kinases, or at least many of them, responsible for this modification have been identified, their cDNAs cloned, and their substrate specificity and subcellular location(s) identified. The phosphoinositide 3-kinases were found early on to be associated with other proteins, notably receptors for growth factors, and this observation has progressed to a detailed list of such binding partners and definition of the regions of the proteins that are essential for the interactions. Likewise, the question of how the phospholipid products from the reaction catalyzed by phosphoinositide 3-kinase(s) alter cell responses has been extensively studied. Many target proteins have been identified, and specific sequences that bind the 3-phosphorylated phospholipids have been determined. Rameh and Cantley review this area, and then it is focused upon by Andrew E. Wurmser, Jonathan D. Gary, and Scott D. Emr in their article, “Phosphoinositide 3-Kinases and Their FYVE Domain-containing Effectors as Regulators of Vacuolar/Lysosomal Membrane Trafficking Patterns.” One particularly productive area of investigation is featured in this review, i.e. the definition of the essential role of these lipids in membrane trafficking, a subject that has been particularly well served by genetic approaches in yeast. The description of the consequences of adding phosphate(s) to phosphatidylinositol is continued in the review, “Phosphatidylinositol Phosphate Kinases, a Multifaceted Family of Signaling Enzymes” by Richard A. Anderson, Igor V. Boronenkov, Scott D. Doughman, Jeannette Kunz, and Joost C. Loijens. It has been known for many years that phosphatidylinositol could be converted to singly and doubly phosphorylated forms with the additions at the 4- and 5-positions of the inositol; in fact, such products are found as trace components of cellular membranes. The recent identification of the kinases that catalyze these reactions has both explained the usual synthetic pathway for these membrane constituents and, as with the 3-kinase story, led to the observation that the synthesis of these lipids was involved in many types of cellular signaling. As with the 3-kinases, these enzymes are found in complexes with other signaling proteins, a general theme that has emerged in studies of lipid kinases and phosphatases, just as with protein kinases and phosphatases. The study of inositol phosphatases began as an effort to define one of the off switches in signaling initiated by the hydrolysis of phosphoinositides; this is one of the phospholipase-initiated pathways mentioned above, and when phosphatidylinositol P2 is cleaved by a phospholipase C the water-soluble product, inositol trisphosphate, is a signal to raise the intracellular calcium concentration. The removal of the 5-phosphate abolishes the signal and calcium declines. After members of this phosphatase family were identified it subsequently was found that some of them also could catalyze the removal of phosphate from the phospholipids, a completely unexpected finding. This property has been implicated in the tumor-suppressing ability of one of the inositol phosphatases, PTEN. This rapidly evolving field is reviewed by Philip W. Majerus, Marina V. Kisseleva, and F. Anderson Norris in their article “The Role of Phosphatases in Inositol Signaling Reactions.” Another signal from the phosphatidylinositol signaling cycle that needs to be shut off is diacylglycerol, the other product of the phospholipase C reaction. This neutral lipid is present only in very low amounts in normal, resting cells but rises in response to many types of stimuli and is elevated persistently in many transformed cells. Its major action is to activate members of the protein kinase C family, which have diverse effects on cell growth, differentiation, and other responses. The major route for lowering the transiently elevated diacylglycerol is by conversion to phosphatidic acid, a reaction that adds phosphate to the lipid. This is catalyzed by a family of kinases that Matthew K. Topham and I review in “Mammalian Diacylglycerol Kinases, a Family of Lipid Kinases with Signaling Functions.” As with the kinases and phosphatases that modify phosphatidylinositol, the diacylglycerol kinases are a diverse group. Two themes run through these reviews of enzymes that add and remove phosphate from lipids. First, they are found in complexes with other signaling proteins including protein kinases and phosphatases, G proteins, and each other. Second, although they all were initially assumed to be part of events localized to the plasma membrane and nearby cytoplasm, they all have additionally been found to be in the nucleus, where they participate in what appears to be a parallel signaling system. Both of these themes will attract intense interest in the next few years as the functional significance is dissected." @default.
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• W2087676876 title "A Thematic Series on Kinases and Phosphatases That Regulate Lipid Signaling" @default.
• W2087676876 doi "https://doi.org/10.1074/jbc.274.13.8345" @default.
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