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Phosphoinositide 3-kinase in Health and Disease Volume 2

:	Christian Rommel, Bart Vanhaesebroeck, Peter K. Vogt
:	Christian Rommel, Bart Vanhaesebroeck, Peter K. Vogt
:	Phosphoinositide 3-kinase in Health and Disease Volume 2
:	Springer-Verlag
:	9783642148163
:	1
:	CHF 201.10
:

:	Nichtklinische Fächer
:	English

:	306
:	Wasserzeichen
:	PC/MAC/eReader/Tablet
:	PDF

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

	Phosphoinositide 3-kinase in Health and Disease	3
	Volume 2	3
	Contents	5
	Contributors	7
	PI3K: From the Bench to the Clinic and Back	11
	1 The Discovery of the PI3K Signalling Pathway and Its Potential as a Therapeutic Target	12
	2 PI3K and Human Disease	14
	3 The Development of PI3K Inhibitors for Human Disease Starts to Inform Basic Science	15
	4 Some Outstanding Questions in PI3K Biology and Signalling	18
	5 Concluding Remarks	20
	References	21
	Oncogenic Mutations of PIK3CA in Human Cancers	30
	1 Introduction	31
	2 Links Between the PI3K Pathway and Cancer	31
	3 High Throughput Sequencing of Gene Families in Human Cancer	32
	4 PIK3CA is Somatically Mutated in Colorectal Cancer	32
	5 PIK3CA is Mutated in a Wide Variety of Human Tumor Types	33
	6 Somatic Mutations in the PI3K Pathway Typically Occur in a Mutually Exclusive Fashion	40
	7 Conclusion	42
	References	43
	Structural Effects of Oncogenic PI3Ka Mutations	51
	1 Introduction	52
	2 Description of the Structure	53
	3 Association with the Lipid Membrane	55
	4 Cancer-Specific Mutations	56
	5 Summary and Conclusions	60
	References	61
	Comparing the Roles of the p110a and p110beta Isoforms of PI3K in Signaling and Cancer	62
	1 Introduction	63
	2 Class IA PI3Ks	64
	3 Mechanisms of Activation of Class IA p110 Isoforms	64
	3.1 Early Studies on In Vitro p110a/beta Activation	64
	3.2 Studies on p110 Activation Using Engineered Mice	67
	3.3 Unresolved Issues	68
	4 Downstream Signaling: Acting Out Through AKT and PDK1	70
	4.1 AKT Signaling	70
	5 PI3K Isoforms in Cancer	71
	5.1 Deregulated PI3K Pathway Components	72
	5.2 Targeting PI3K in Cancer	73
	5.3 p110a as a Viable Tumor Target	73
	5.4 p110beta as a Drug Target	75
	5.5 What Are the Take-Home Messages from p110-Isoform Knock-Out Studies In Vivo?	76
	5.6 Kinase-Independent Roles of p110-Isoforms	76
	6 Conclusions	78
	References	78
	Phosphatidylinositol 3-Kinase: The Oncoprotein	85
	1 Phosphatidylinositol 3-Kinases and Cancer	86
	2 Cancer-Specific Mutations in PI3K	87
	3 Several Molecular Mechanisms Can Induce a Gain of Function in p110	90
	4 Non-alpha Isoforms of Class I PI3K in Cancer	92
	5 Class II and III PI3Ks	94
	6 PI3K-Driven Oncogenic Transformation: Mechanistic Considerations	95
	7 Conclusion	99
	References	100
	AKT Signaling in Physiology and Disease	111
	1 Introduction	112
	2 AKT Kinases	113
	2.1 Isoforms	113
	2.2 Domain Structure	113
	3 Mechanisms of AKT Activation	114
	3.1 PDK1-Dependent AKT Phosphorylation	116
	3.2 Hydrophobic Motif Phosphorylation	116
	3.3 Phosphorylation of Other AKT Residues	117
	4 Negative Regulation of AKT Signaling	117
	4.1 Lipid Phosphatases	117
	4.2 AKT-Specific Protein Phosphatases	118
	4.3 AKT Inhibition by Interacting Proteins	118
	4.4 Lipid Binding PH Domain-Only Proteins	119
	4.5 Feedback Regulation of AKT Signaling	119
	5 AKT Substrates	119
	6 AKT Signaling in Physiology	121
	6.1 Glucose Homeostasis and Metabolism	121
	6.2 Cell Proliferation	122
	6.3 Cell Survival	122
	6.4 Cell Migration and Invasion	123
	6.5 Cell Growth and Protein Translation	124
	6.6 Angiogenesis	125
	6.7 Apoptosis and Senescence Induction	125
	6.8 Immunity	126
	6.9 Brain Development, Neuronal Differentiation, and Function	126
	7 Roles of the AKT Signaling Pathway in Human Disease	127
	7.1 Diabetes	127
	7.2 Neurological Diseases	128
	7.3 Cancer	128
	7.3.1 Genetic Alterations in the Upstream RTK Signaling Axis	129
	7.3.2 Inactivating Mutations of PTEN	129
	7.3.3 Activating Mutations of PI3K	129
	7.3.4 Activating Mutations of AKT	130
	7.3.5 Mouse Tumor Models of AKT Activation	130
	8 AKT Independent Signaling by PI3K	131
	9 Conclusions	132
	References	132
	Faithfull Modeling of PTEN Loss Driven Diseases in the Mouse	140
	1 Introduction	141
	2 Spectrum of Human Diseases Associated with Loss of PTEN	142
	3 Modeling PTEN Loss in Specific Murine Organs	143
	3.1 Brain	143
	3.2 Prostate	151
	3.3 Breast	153
	4 In Vivo Deconstruction of the PI3K-AKT-mTOR Axis	154
	4.1 PI3K-PDK-AKT	154
	4.2 TSC1/2-Rheb-mTOR	155
	5 PTEN Network: Linking the PI3K Signaling Cascade to Other Oncogenic Pathways Through In Vivo Genetic Analysis	157
	5.1 PTEN-MAPK Pathway	157
	5.2 Pten and Transcriptional Regulators: Erg and Myc	159
	5.3 Pten/p53	160
	6 Context-Dependent Differential Outcomes Triggered by Loss of PTEN	161
	7 Conclusion	163
	References	163
	PI3K as a Target for Therapy in Haematological Malignancies	174
	1 Introduction	175
	2 Acute Myeloid Leukaemia	177
	3 Acute Lymphoblastic Leukaemia	179
	4 Chronic Myeloid Leukaemia and BCR-ABL Positive ALL	180
	5 Chronic Lymphocytic Leukaemia	181
	6 Lymphomas	182
	6.1 Diffuse Large B Cell Lymphoma	182
	6.2 Anaplastic Large Cell Lymphoma	183
	6.3 Mantle Cell Lymphoma	183
	7 Multiple Myeloma	183
	8 Effects on Normal Immune Cells and Host Immunity	184
	9 Conclusions	185
	References	186
	Clinical Development of Phosphatidylinositol-3 Kinase Pathway Inhibitors	194
	1 Introduction	195
	2 Pharmacological Approaches	195
	3 Preclinical Considerations for Drug Development	197
	4 Clinical Trials	199
	5 Patient Selection and Role of Presurgical Trials	200
	6 Rationale for Combination Therapies	203
	7 Neoadjuvant Clinical Trials	205
	8 Conclusions	206
	References	207
	From the Bench to the Bed Side: PI3K Pathway Inhibitors in Clinical Development	214
	1 Introduction	214
	2 PI3K Inhibitors: Path to the Clinic	216
	2.1 PI3K Inhibitors in Oncology Drug Discovery and Development