1;Phosphoinositide 3-kinase in Health and Disease;3 1.1;Volume 2;3 1.2;Contents;5 1.3;Contributors;7 1.4;PI3K: From the Bench to the Clinic and Back;11 1.4.1;1 The Discovery of the PI3K Signalling Pathway and Its Potential as a Therapeutic Target;12 1.4.2;2 PI3K and Human Disease;14 1.4.3;3 The Development of PI3K Inhibitors for Human Disease Starts to Inform Basic Science;15 1.4.4;4 Some Outstanding Questions in PI3K Biology and Signalling;18 1.4.5;5 Concluding Remarks;20 1.4.6;References;21 1.5;Oncogenic Mutations of PIK3CA in Human Cancers;30 1.5.1;1 Introduction;31 1.5.2;2 Links Between the PI3K Pathway and Cancer;31 1.5.3;3 High Throughput Sequencing of Gene Families in Human Cancer;32 1.5.4;4 PIK3CA is Somatically Mutated in Colorectal Cancer;32 1.5.5;5 PIK3CA is Mutated in a Wide Variety of Human Tumor Types;33 1.5.6;6 Somatic Mutations in the PI3K Pathway Typically Occur in a Mutually Exclusive Fashion;40 1.5.7;7 Conclusion;42 1.5.8;References;43 1.6;Structural Effects of Oncogenic PI3Ka Mutations;51 1.6.1;1 Introduction;52 1.6.2;2 Description of the Structure;53 1.6.3;3 Association with the Lipid Membrane;55 1.6.4;4 Cancer-Specific Mutations;56 1.6.5;5 Summary and Conclusions;60 1.6.6;References;61 1.7;Comparing the Roles of the p110a and p110beta Isoforms of PI3K in Signaling and Cancer;62 1.7.1;1 Introduction;63 1.7.2;2 Class IA PI3Ks;64 1.7.3;3 Mechanisms of Activation of Class IA p110 Isoforms;64 1.7.3.1;3.1 Early Studies on In Vitro p110a/beta Activation;64 1.7.3.2;3.2 Studies on p110 Activation Using Engineered Mice;67 1.7.3.3;3.3 Unresolved Issues;68 1.7.4;4 Downstream Signaling: Acting Out Through AKT and PDK1;70 1.7.4.1;4.1 AKT Signaling;70 1.7.5;5 PI3K Isoforms in Cancer;71 1.7.5.1;5.1 Deregulated PI3K Pathway Components;72 1.7.5.2;5.2 Targeting PI3K in Cancer;73 1.7.5.3;5.3 p110a as a Viable Tumor Target;73 1.7.5.4;5.4 p110beta as a Drug Target;75 1.7.5.5;5.5 What Are the Take-Home Messages from p110-Isoform Knock-Out Studies In Vivo?;76 1.7.5.6;5.6 Kinase-Independent Roles of p110-Isoforms;76 1.7.6;6 Conclusions;78 1.7.7;References;78 1.8;Phosphatidylinositol 3-Kinase: The Oncoprotein;85 1.8.1;1 Phosphatidylinositol 3-Kinases and Cancer;86 1.8.2;2 Cancer-Specific Mutations in PI3K;87 1.8.3;3 Several Molecular Mechanisms Can Induce a Gain of Function in p110;90 1.8.4;4 Non-alpha Isoforms of Class I PI3K in Cancer;92 1.8.5;5 Class II and III PI3Ks;94 1.8.6;6 PI3K-Driven Oncogenic Transformation: Mechanistic Considerations;95 1.8.7;7 Conclusion;99 1.8.8;References;100 1.9;AKT Signaling in Physiology and Disease;111 1.9.1;1 Introduction;112 1.9.2;2 AKT Kinases;113 1.9.2.1;2.1 Isoforms;113 1.9.2.2;2.2 Domain Structure;113 1.9.3;3 Mechanisms of AKT Activation;114 1.9.3.1;3.1 PDK1-Dependent AKT Phosphorylation;116 1.9.3.2;3.2 Hydrophobic Motif Phosphorylation;116 1.9.3.3;3.3 Phosphorylation of Other AKT Residues;117 1.9.4;4 Negative Regulation of AKT Signaling;117 1.9.4.1;4.1 Lipid Phosphatases;117 1.9.4.2;4.2 AKT-Specific Protein Phosphatases;118 1.9.4.3;4.3 AKT Inhibition by Interacting Proteins;118 1.9.4.4;4.4 Lipid Binding PH Domain-Only Proteins;119 1.9.4.5;4.5 Feedback Regulation of AKT Signaling;119 1.9.5;5 AKT Substrates;119 1.9.6;6 AKT Signaling in Physiology;121 1.9.6.1;6.1 Glucose Homeostasis and Metabolism;121 1.9.6.2;6.2 Cell Proliferation;122 1.9.6.3;6.3 Cell Survival;122 1.9.6.4;6.4 Cell Migration and Invasion;123 1.9.6.5;6.5 Cell Growth and Protein Translation;124 1.9.6.6;6.6 Angiogenesis;125 1.9.6.7;6.7 Apoptosis and Senescence Induction;125 1.9.6.8;6.8 Immunity;126 1.9.6.9;6.9 Brain Development, Neuronal Differentiation, and Function;126 1.9.7;7 Roles of the AKT Signaling Pathway in Human Disease;127 1.9.7.1;7.1 Diabetes;127 1.9.7.2;7.2 Neurological Diseases;128 1.9.7.3;7.3 Cancer;128 1.9.7.3.1;7.3.1 Genetic Alterations in the Upstream RTK Signaling Axis;129 1.9.7.3.2;7.3.2 Inactivating Mutations of PTEN;129 1.9.7.3.3;7.3.3 Activating Mutations of PI3K;129 1.9.7.3.4;7.3.4 Activating Mutations of