Phosphoinositides

This volume describes the current status of the biology of inositols and phosphoinositides with an emphasis on the development in the area since the publication of volume 26 in 1996 in this series. The progress made in dissecting the genetics, structure and evolution of the seminal enzyme for synthesis of inositol in the biological system has driven the understanding of the enzyme forward. With the current genomic and proteomic tools in place the new role of inositols, inositol phosphates and phosphoinositides in cell signaling or stress response has been explored. These advances are described in this volume and are expected to give new insights into the functional implications of inositol compounds across evolutionary diverse species.

This is a review of the current opinions on lipid signalling research with an emphasis on the integration of the use of lipid signals in signal transduction and membrane trafficking. These two areas have traditionally been seen as separate, but in the light of recent research it has become apparent that any work in this area must include the two, as this book does. In the text, control of synthesis, translocation, and degradation of phosphoinositides is given extensive coverage; there is specific discussion of the PH and FYVE lipid binding domains that allow lipids to control the movement, location, and activation-state of membrane proteins; the regulation of phospholipase C, phospholipase D, the phosphoinositide-3-kinases, chloride channel conductance by inositol (3,4,5,6) tetraphosphate, and of cytoskeletal protein activity by inositol lipids are all covered in depth.

Cells of the immune system are activated by a variety of stimuli that are derived from other cells, ingested material or from invading microorganisms. This issue of CTMI focuses on the mechanisms of phosphoinositide-mediated protein recruitment to intracellular membranes.

Phosphoinositides play a major role in cellular signaling and membrane organization. During the last three decades we have learned that enzymes turning over phosphoinositides control vital physiological processes and are involved in the initiation and progression of cancer, inflammation, neurodegenerative, cardiovascular, metabolic disease and more. In two volumes, this book elucidates the crucial mechanisms that control the dynamics of phosphoinositide conversion. Starting out from phosphatidylinositol, a chain of lipid kinases collaborates to generate the oncogenic lipid phosphatidylinositol(3,4,5)-trisphosphate. For every phosphate group added, there are specific lipid kinases – and phosphatases to remove it. Additionally, phospholipases can cleave off the inositol head group and generate poly-phosphoinositols, which act as soluble signals in the cytosol. Volume II extends into the role of phosphoinositides in membrane organization and vesicular traffic. Endocytosis and exocytosis are modulated by phosphoinositides, which determine the fate and activity of integral membrane proteins. Phosphatidylinositol(4,5)-bisphosphate is a prominent flag in the plasma membrane, while phosphatidylinositol-3-phosphate decorates early endosomes. The Golgi apparatus is rich in phosphatidylinositol-4-phosphate, stressed cells increase phosphatidylinositol(3,5)-bisphosphate, and the nucleus has a phosphoinositide metabolism of its own. Phosphoinositide-dependent signaling cascades and the spatial organization of distinct phosphoinositide species are required in organelle function, fission and fusion, membrane channel regulation, cytoskeletal rearrangements, adhesion processes, and thus orchestrate complex cellular responses including growth, proliferation, differentiation, cell motility, and cell polarization.

Phosphoinositides (PIs) are minor components of cellular membranes that play critical regulatory roles in several intracellular functions. This book describes the main enzymes regulating the turnover of each of the seven PIs in mammalian cells, some of their intracellular functions and some evidence of their involvement in human diseases. Due to the complex inter-relation between the distinct PIs and the plethora of functions that they can regulate inside a cell, this book is not meant to be a comprehensive coverage of all aspects of PIs signalling but rather an overview on the current state of the field and where it could go from here. Phosphoinositide and inositol phosphates interact with and modulate the recruitment and activation of key regulatory proteins and in doing so control diverse functions including cell growth and proliferation, apoptosis, cytoskeletal dynamics, insulin action, vesicle trafficking and nuclear function. Initially, inositide signaling was limited to the PLC pathway; however, it is now clear that all the seven phosphoinositides and more than 30 different inositol phosphates likely have specific signaling functions. Moreover there is a growing list of proteins that are regulated by inositol signaling. This has raised the question as to how inositol signaling can control diverse processes and yet maintain signaling specificity. Controlling the levels of inositol signaling molecules and their subcellular compartmentalisation is likely to be critical. This meeting will bring together scientists from different backgrounds to discuss how understanding inositol signaling may be used to target complex human diseases that manifest themselves when inositol signaling is deregulated.

The Chilton Conference on Inositol and Phosphoinositides, held on January 9-11, 1984 at Southwestern Medical School, University of Texas Health Science Center, Dallas, Texas, was the third in a series of conferences on cyclitols and phosphoinositides. The first took place in 1968 in New York [Ann. New York Acad. Sci. (1969), 765,508-819] and the second was held in 1977 in East Lansing, Michigan [eyclitols and Phosphoinositides, Wells, W. W. and Eisenberg, F. , eds. , (1978) Academic press, New York, pp. 1-607. ] In the interim since the previous conference, not only has the pace of research in the field accelerated markedly, but the physiological importance of phosphoinositide metabolism has become apparent to an increasing number of investigators from diverse fields in the life sciences. Thus it seemed to us timely for both recent and established workers in this area, as well as others whose interests impinged on it, to meet in order to disseminate new information, to review, and perhaps arrive at, a consensus of our current understanding of the role of inositol and phosphoinositides, and to establish new directions for research for the next few years. The expansion of the field since the last meeting made it mandatory to restrict the scope of the topics covered at the conference, primarily to aspects dealing with mammalian systems. We sincerely regretted the exclusion of recent research on cyclitols and phosphoinositides in microbes and plants and hope that these areas will be included in future conferences.

Phosphoinositides play a major role in cellular signaling and membrane organization. During the last three decades we have learned that enzymes turning over phosphoinositides control vital physiological processes and are involved in the initiation and progression of cancer, inflammation, neurodegenerative, cardiovascular, metabolic disease and more. In two volumes, this book elucidates the crucial mechanisms that control the dynamics of phosphoinositide conversion. Starting out from phosphatidylinositol, a chain of lipid kinases collaborates to generate the oncogenic lipid phosphatidylinositol(3,4,5)-trisphosphate. For every phosphate group added, there are specific lipid kinases – and phosphatases to remove it. Additionally, phospholipases can cleave off the inositol head group and generate poly-phosphoinositols, which act as soluble signals in the cytosol. Volume I untangles the web of these enzymes and their products, and relates them to function in health and disease. Phosphoinositide 3-kinases and 3-phosphatases have received a special focus in volume I, and recent therapeutic developments in human disease are presented along with a historical perspective illustrating the impressive progress in the field.

`The heterogeneity of topics ... is very ambitious, and the result is, overall, successful because of the high quality of the individual contributions ... highly recommended.' -American Scientist, from a review of a previous volume Volume 26 examines the emerging areas of signal transduction based on myoinositol phosphates and Ca2+ while focusing on plant and animal responses. Chapters explore synthesis, separation, and identification of different inositol phosphates.