PI3K has become a very intense area of research, with over 2000 publications on PI3K in PubMed for 2009 alone. The expectations for a therapeutic impact of intervention with PI3K activity are high, and progress in the clinical arena is being monitored by many. However, targeted therapies almost invariably encounter roadblocks, often exposing unresolved questions in the basic understanding of the target
From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here we give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here
From humble beginnings over 25 years ago as a lipid kinase activity associated with certain oncoproteins, PI3K (phosphoinositide 3-kinase) has been catapulted to the forefront of drug development in cancer, immunity and thrombosis, with the first clinical trials of PI3K pathway inhibitors now in progress. Here we give a brief overview of some key discoveries in the PI3K area and their impact, and include thoughts on the current state of the field, and where it could go from here
PI3K has become a very intense area of research, with over 2000 publications on PI3K in PubMed for 2009 alone. The expectations for a therapeutic impact of intervention with PI3K activity are high, and progress in the clinical arena is being monitored by many. However, targeted therapies almost invariably encounter roadblocks, often exposing unresolved questions in the basic understanding of the target
This book provides an essential overview of the role of phosphoinositide-3-phosphate kinase (PI3K) isoforms in modulating the function of immune system cells and their involvement in disease. PI3K is a family of kinases involved in basic cellular processes such as proliferation, migration and cell death. Recent work has highlighted the multiple roles of PI3K classes and subunits and their involvement in the immune response to the body’s own and foreign antigens and diseases such as cancer and autoimmunity. This book offers a detailed introduction to the biology of the three PI3K classes, followed by an extensive discussion of the diverse roles of AKT and PI3K isoforms in immune cells. Based on this knowledge, it subsequently explains in more detail how specific isoforms are connected to immune-mediated diseases. The book concludes by highlighting the latest advances in the production of isoform-specific inhibitors and their use in various human diseases. This book is intended as a reference guide for students and researchers interested in the multifaceted aspects of PI3K biology.
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 PI3Ks control many key functions in immune cells. PI3Ks phosphorylate PtdIns(4,5)P2 to yield PtdIns(3,4,5)P3. Initially, PI3K inhibitors such as Wortmannin, LY294002 and Rapamycin were used to establish a central role for Pi3K pathway in immune cells. Considerable progress in understanding the role of this pathway in cells of the immune system has been made in recent years, starting with analysis of various PI3K and Pten knockout mice and subsequently mTOR and Foxo knockout mice. Together, these experiments have revealed how PI3Ks control B cell and T cell development, T helper cell differentiation, regulatory T cell development and function, B cell and T cell trafficking, immunoglobulin class switching and much, much more. The PI3Kd inhibitor idelalisib has recently been approved for the treatment of B cell lymphoma. Clinical trials of other PI3K inhibitors in autoimmune and inflammatory diseases are also in progress. This is an opportune time to consider a Research Topic considering when what we have learned about the PI3K signalling module in lymphocyte biology and how this is making an impact on clinical immunology and haematology.
Autophagy: Cancer, Other Pathologies, Inflammation, Immunity, Infection, and Aging is an eleven volume series that discusses in detail all aspects of autophagy machinery in the context of health, cancer, and other pathologies. Autophagy maintains homeostasis during starvation or stress conditions by balancing the synthesis of cellular components and their deregulation by autophagy. This series discusses the characterization of autophagosome-enriched vaccines and its efficacy in cancer immunotherapy. Autophagy serves to maintain healthy cells, tissues, and organs, but also promotes cancer survival and growth of established tumors. Impaired or deregulated autophagy can also contribute to disease pathogenesis. Understanding the importance and necessity of the role of autophagy in health and disease is vital for the studies of cancer, aging, neurodegeneration, immunology, and infectious diseases. Comprehensive and forward-thinking, these books offer a valuable guide to cellular processes while also inciting researchers to explore their potentially important connections. Presents the most advanced information regarding the role of the autophagic system in life and death Examines whether autophagy acts fundamentally as a cell survivor or cell death pathway or both Introduces new, more effective therapeutic strategies in the development of targeted drugs and programmed cell death, providing information that will aid in preventing detrimental inflammation Features recent advancements in the molecular mechanisms underlying a large number of genetic and epigenetic diseases and abnormalities, including atherosclerosis and CNS tumors, and their development and treatment Includes chapters authored by leaders in the field around the globe—the broadest, most expert coverage available
Aimed at advanced undergraduates, postgraduates and researchers, this important textbook provides a detailed description of the structure and mechanisms of phosphoinositide 3-kinase (PI3Ks) signalling of all classes, with focus on the cellular context of PI3K activity, including its relevance to normal tissue and diseased states. This book contains a general review chapter detailing the mechanisms of cell proliferation and apoptosis, which are two of the main cellular targets of PI3K signalling. In addition, it provides a detailed description of the role of PI3K on the regulation of FOXO proteins, which are now becoming one of the most closely studied and important proteins in the regulation of cell death, cell proliferation and senescence. Contents: Introduction (E W-F Lam); Cell Proliferation and Cell Death; In Vivo Roles of Cell Cycle and Apoptosis Regulators; The Role of Phosphoinositide 3-Kinase in Proliferation and Apoptosis (A Sunters & E W-F Lam); Phosphoinositide 3-Kinase Signalling Pathway; Class IA PI3K Enzymes; Class IB PI3K Enzymes; Class II PI3K Enzymes; Class III PI3K Enzymes; Expression of PI3K Enzymes; 3-Phosphoinositide Binding Domains; Downstream Targets of 3-Phosphoinositide; Manipulation of PI3K Enzyme Expression; Biological Role of PI3K Signalling Pathway; Phosphoinositide Phosphatases; The Role of the PI3K Pathway in Disease (J Domin); PI3K Signalling to Cell Survival and Proliferation; Molecules Directly Regulated by D3 Lipids; Genetic Studies of PI3K Function in Model Organisms; Molecules Downstream of PI3K and D3 Lipids; PI3K Regulation of Cell Survival; Signalling from PI3K to Cell Proliferation; Alterations of PI3K and Its Pathways in Cancer; Cancer Therapeutics (P Brennan); FOXO Transcription Factors; Forkhead Transcription Factors; FOXO Transcription Factors; Signalling to FOXO Proteins; Cellular Relocation Mechanism; FOXO Protein Processing; Transcriptional Activity of FoxO Proteins; Functions of FOXO in Vivo; FOXO Targets and Function; FOXO Proteins in Transformation and Diseases (S Fernandez de Mattos et al.). Key Features Provides a clear and well-organized review of PI3K signalling garnered from an exhaustive review of the available literature Readership: Undergraduates, postgraduates, academic researchers, clinicians and scientists working in industry.
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.
