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Phosphoinositide 3-kinase in Health and Disease Volume 1

:	Christian Rommel, Bart Vanhaesebroeck, Peter K. Vogt
:	Christian Rommel, Bart Vanhaesebroeck, Peter K. Vogt
:	Phosphoinositide 3-kinase in Health and Disease Volume 1
:	Springer-Verlag
:	9783642136634
:	1
:	CHF 200.50
:

:	Nichtklinische Fächer
:	English

:	310
:	Wasserzeichen/DRM
:	PC/MAC/eReader/Tablet
:	PDF

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

	Contents	6
	Contributors	8
	Introduction	12
	1 Establishing Order Within the Cell	12
	2 Phosphatidylinositol and Phosphoinositides as Ideal Substrates	13
	3 Nucleating a Protein Complex at a Target Location	14
	4 Coupling PI3K Activity to Extracellular Cues	14
	5 Disease Implications	16
	References	17
	PDK1: The Major Transducer of PI 3-Kinase Actions	19
	1 Introduction	20
	2 Mechanism of Activation of the AGC Kinases	20
	2.1 PDK1, the Common T-Loop Kinase	21
	2.2 mTORC1 and mTORC2, the Hydrophobic Motif Kinases	22
	2.3 Two Mechanisms of Regulation by PDK1	24
	3 Structure of PDK1	26
	4 Genetic Models and Disease	27
	4.1 PDK1 and Diabetes	27
	4.2 PDK1 and T-Cell Development	29
	4.3 PDK1, Growth and Cancer	29
	5 PDK1 as a Druggable Target	30
	6 Concluding Remarks	32
	References	33
	Protein Kinase B (PKB/Akt), a Key Mediator of the PI3K Signaling Pathway	40
	1 Classification, Structure, and Substrates of PKB	41
	2 Regulation of PKB Activity	42
	2.1 Regulation of PKB Activity by Phosphorylation Events	42
	2.2 Regulation of PKB Activity by Binding Partners	44
	2.2.1 PKB Activators	45
	2.2.2 PKB Inhibitors	47
	2.2.3 PKB-Interacting Proteins with Undefined Functions	47
	2.3 Regulation of PKB by CTMP	48
	3 The Role of PKB in Physiological and Pathological Conditions	49
	3.1 Effects of Knocking-Out Individual PKB Isoforms in Mice	50
	3.2 PKB in Embryonic Development	50
	3.3 PKB in Thymocyte Development	51
	3.4 PKB in Adipocyte Differentiation	52
	3.5 PKB in Glucose Homeostasis	53
	3.6 PKB in Tumor Formation	55
	4 Conclusion	56
	References	57
	PI3Ks in Lymphocyte Signaling and Development	66
	1 Introduction	68
	2 PI3K in B Cells	71
	2.1 B-Cell Development	71
	2.2 BcR Signaling, Antigen Presentation, and Metabolism	72
	2.3 Immunoglobulin Gene Rearrangement and Isotype Switching	74
	2.4 B-Cell Chemotaxis and Trafficking	76
	3 PI3K in T Cells	76
	3.1 T-Cell Development and Differentiation	76
	3.1.1 A Surprising Redundancy Between p110delta and p110gamma During T-Cell Development	76
	3.2 TcR Signaling and Costimulation	77
	3.2.1 PI3K Regulates Some, But Not All, TcR-Dependent Signaling Pathways	79
	3.3 T-Helper Cell Differentiation	80
	3.4 Survival and Glucose Homeostasis in Mature T cells	81
	3.5 PI3K Controls the Development and Suppressive Function of Regulatory T Cells	81
	3.6 T-Cell Chemotaxis and Migration in Lymph Nodes: Not All About PI3K	83
	3.7 T-Cell Trafficking	84
	3.8 Nonessential Role for PI3K in Cytotoxic Responses	85
	4 Prospects for PI3K Inhibitors in Inflammation and Autoimmunity	85
	References	86
	The Regulation of Class IA PI 3-Kinases by Inter-Subunit Interactions	95
	1 Structural Organization of p85a/p110a	96
	2 p85a Inhibits and Stabilizes p110	98
	3 Activation of p85a/p110a Dimers by Phosphopeptides	100
	4 A Mechanism for Phosphopeptide Activation	101
	5 Activation of p85/p110 by GTPases	104
	6 Activation by Binding to p85 SH3 and Proline-Rich Domains	107
	7 Regulation by Autophosphorylation	107
	8 Oncogenic Mutation of p85a and p110	108
	8.1 Helical Domain Mutants: Disruption of the nSH2-Helical Domain Interface	109
	8.2 The Kinase Domain Mutant H1047R	110
	8.3 p110a Mutations Disrupting the C2-iSH2 Domain Interface	110
	8.4 p85a Mutations Disrupting the C2-iSH2 Domain Interface	111
	9 Regulation of p85/p110 In vivo: Activation Versus Translocation	112
	10 Unanswered Mechanistic Questions on p85-p110 Interactions	113
	References	115
	Phosphoinositide Signalling Pathways in Metabolic Regulation	123
	1 Introduction	124
	2 Role of Insulin Signalling Network Molecules in Metabolic Regulation as Revealed by Global Gene Inactivation in Mice	125
	3 Role of INSR/PI3K Pathway Components in the Development and Function of Insulin Sensitive Tissues	131
	3.1 Insulin Sensitive Peripheral Tissues	131
	3.2 Pancreatic Islets	134
	3.3 Central Nervous System	137
	4 Role of the INSR/PI3K Pathway in the Integration of Nutrient Availability and Growth Factor/Hormonal Signals	139
	5 Molecular Basis of Insulin Resistance Development: Signal Termination Feedback Loops	140
	6 Discussion	141
	References	142
	Role of RAS in the Regulation of PI 3-Kinase	150
	1 RAS Proteins	151
	2 RAS Effectors	153
	3 RAS-PI3K Interaction	157
	4 RAS-PI3K in Normal Signalling	158
	5 RAS-PI3K in Oncogenesis	160
	6 RAS-PI3K-RAF Pathway Interconnections	164
	7 Inhibitors	167
	8 Conclusions	168
	References	169
	More Than Just Kinases: The Scaffolding Function of PI3K	177
	1 The Double Identity of PI3Kgamma	178
	1.1 Cardiomyocytes	179
	1.2 Circulating Endothelial Progenitor Cells	179
	1.3 Platelets	180
	2 The Double Identity of PI3Kbeta	180
	2.1 Cell Growth	180
	2.2 Metabolism	182
	2.3 Oncogenesis	183
	3 The Double Identity of Adaptor Subunits	183
	4 Conclusions	184
	References	185
	PI3K Signaling in Neutrophils	188
	1 Neutrophil Biology	189
	2 Regulation of PI3Ks	192
	3 Regulation of PtdIns(3,4,5)P3	195
	4 Effectors of PI3K Signaling Pathways	195
	5 Class I PI3K Regulation of Rho Family GTPases in the Context of Cell Spreading and Movement	196
	6 Class I and Class III PI3K Regulation of the NADPH Oxidase	198
	7 PI3Ks in Neutrophils as Therapeutic Targets	201
	8 Conclusions	202
	References	202
	PI 3-Kinase p110beta Regulation of Platelet Integrin aIIbbeta3	208
	1 Introduction	209
	2 Basic Principles of Platelet Adhesion and Activation	210
	3 Integrin aIIb