International authors provide researchers with an overview and synthesis of the latest research findings and contemporary thought in the area of Notch Signaling.Covers topics such as Notch signaling in Cardiac development and disease, and Notch in Stem Cells. International authors provide researchers with an overview and synthesis of the latest research findings and contemporary thought in the area.

Contributors	p. xi
Prologue	p. xv
Notch: The Past, the Present, and the Future	p. 1
The Beginnings: Embryology and Genetics	p. 2
The Developmental Logic of Notch: A Constant Frame of Reference	p. 7
The Notch Receptor: Key Features	p. 9
Cloning the Ligands: Engaging Notch	p. 11
Ligand-Receptor Interactions: Not a One-Way Street	p. 14
Targets, Signal Integration, and the Genetic Circuitry of Notch: On Being Old	p. 15
Disease and Notch: The Pathobiology of Gain and Loss of Function	p. 18
Notch and Cancer: Affecting Proliferation Where it Matters?	p. 20
Notch: What's Next	p. 22
Acknowledgments	p. 23
References	p. 23
Mechanistic Insights into Notch Receptor Signaling from Structural and Biochemical Studies	p. 31
Introduction	p. 32
Notch-Ligand Interactions	p. 35
The Activation Event	p. 40
Effector Function	p. 45
Therapeutic Implications of Structural Insights	p. 59
Summary	p. 61
References	p. 62
Canonical and Non-Canonical Notch Ligands	p. 73
Introduction	p. 74
Canonical Notch Ligand Structure	p. 76
Canonical Ligands as Inhibitors of Notch Signaling	p. 79
Regulation of Ligand-Induced Notch Signaling by Posttranslational Modification	p. 83
Ligand Endocytosis in Activation of Notch Signaling	p. 87
Regulation of DSL Ligand Activity by Proteolysis	p. 93
DSL Ligand Interactions with PDZ-Domain Containing Proteins	p. 99
Regulation of DSL Ligand Expression Patterns	p. 100
Noncanonical Ligands	p. 105
Conclusions and Future Directions	p. 113
Acknowledgments	p. 114
References	p. 114
Roles of Glycosylation in Notch Signaling	p. 131
Introduction	p. 132
Glycans of Notch Receptors and DSL Notch Ligands	p. 135
Consequences of Glycan Removal for Notch Signaling	p. 143
Mechanisms of Glycan Regulation of Notch Signaling	p. 151
Acknowledgments	p. 156
References	p. 156
Endocytosis and Intracellular Trafficking of Notch and Its Ligands	p. 165
Notch Signaling and its Regulation by Endocytosis and Vesicle Trafficking	p. 166
Ligand Endocytosis and Trafficking	p. 171
Notch Receptor Endocytosis and Endosomal Trafficking	p. 177
Regulation of Notch Signaling by Endocytosis and Vesicle Trafficking During Mechanosensory Organ Development in Drosophila	p. 185
Conclusion and Future Directions	p. 190
Acknowledgments	p. 191
References	p. 191
¿-Secretase and the Intramembrane Proteolysis of Notch	p. 201
Introduction	p. 202
Regulated Intramembrane Proteolysis of Notch	p. 202
Discovery of ¿-Secretase	p. 203
¿-Secretase Cleaves Many Substrates	p. 204
Unraveling the ¿-Secretase Complex	p. 205
¿-Secretases Are Tetrameric Complexes	p. 209
Structure and Assembly of the Complex	p. 211
Consecutive Cleavage Model for ¿-Secretase	p. 212
Regulation of ¿-Secretase Activity	p. 213
¿-Secretase as a Drug Target: AD and Cancer	p. 214
Conclusion	p. 217
Acknowledgments	p. 218
References	p. 218
Two Opposing Roles of RBP-J in Notch Signaling	p. 231
The Identification of RBP-J and its Connection to Notch Signaling	p. 232
RBP-J as a Transcription Factor	p. 233
Biological Functions of RBP-J in Drosophila	p. 235
Regulation of Mammalian Neuronal Development by RBP-J	p. 237
Regulation of Mammalian Hematopoietic Cell Development by RBP-J	p. 240
Notch-Independent RBP-J Functions	p. 242
Acknowledgments	p. 244
References	p. 244
Notch Targets and Their Regulation	p. 253
Introduction	p. 253
Number and Diversity of Notch Targets	p. 254
How Does the Notch Switch Work?	p. 258
Different Enhancer Logics	p. 262
Context Dependence of Notch Responses	p. 263
Concluding Comments	p. 266
References	p. 266
Notch Signaling in the Vasculature	p. 277
Introduction	p. 278
Arteriovenous Differentiation	p. 280
Endothelial Tip Cell Differentiation	p. 286
Tumor Angiogenesis	p. 290
Notch Signaling and Vascular Smooth Muscle Cells	p. 292
Medical Consequences of Aberrant NOCH₃ Signaling in Vascular Smooth Muscle Cells: CADASIL	p. 295
Perspectives and Conclusions	p. 301
Acknowledgments	p. 301
References	p. 301
Ultradian Oscillations in Notch Signaling Regulate Dynamic Biological Events	p. 311
Introduction	p. 312
Hes7 Oscillations Regulate Somite Segmentation	p. 314
Hes1 Oscillations Regulate Neural Stem Cells	p. 320
Hes1 Oscillations Regulate ES Cell Differentiation	p. 325
Conclusions	p. 327
References	p. 328
Notch Signaling in Cardiac Development and Disease	p. 333
Outline of Cardiac Development	p. 334
Cardiomyocyte Specification and Differentiation	p. 335
Atrioventricular Canal Development	p. 336
Cardiac Valve Development	p. 339
Ventricular Chamber Development: Trabeculation	p. 341
Outflow Tract Development	p. 344
Left Ventricular Outflow Tract Obstruction (Lvoto)	p. 348
Right Ventricular Outflow Tract Obstruction	p. 351
Acquired Disease	p. 355
Conclusions	p. 357
Acknowledgments	p. 358
References	p. 358
Notch Signaling in the Regulation of Stem Cell Self-Renewal and Differentiation	p. 367
Introduction to stem cells and stem cell biology	p. 368
The Notch Pathway in Stem Cell Regulation and Function	p. 378
Conclusions and Perspective	p. 395
References	p. 397
Notch Signaling in Solid Tumors	p. 411
Introduction	p. 412
Notch and Breast Cancer	p. 415
Notch Signaling in Cutaneous Melanoma	p. 422
Notch and Colon Cancer	p. 425
Notch Signaling in Pancreatic Cancer	p. 431
Notch Signaling in Medulloblastoma	p. 435
Notch and Its Tumor-suppressive Properties in the Skin	p. 437
Therapeutically Targeting Notch in Cancer	p. 442
Concluding Remarks	p. 445
Acknowledgments	p. 445
References	p. 446
Biodiversity and Noncanonical Notch Signaling	p. 457
A Wide Range of Notch-dependent Activities	p. 458
Noncanonical Notch Signaling and Bristle Patterning	p. 460
Noncanonical N Signals in Vertebrates	p. 463
Misappropriation by Viruses	p. 469
New Insights on MAML	p. 469
Rheostat and Fine-tuning	p. 469
Nonnuclear Mechanisms	p. 470
Discussion	p. 472
Acknowledgments	p. 475
References	p. 475
Index	p. 483
Contents of Previous Volumes	p. 497
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