Ip / Tsai Cyclin Dependent Kinase 5 (Cdk5)

1. Auflage 2009
ISBN: 978-0-387-78887-6
Verlag: Springer
Format: PDF
Kopierschutz: 1 - PDF Watermark

E-Book, Englisch, 313 Seiten

Cyclin Dependent Kinase 5 provides a comprehensive and up-to-date collection of reviews on the discovery, signaling mechanisms and functions of Cdk5, as well as the potential implication of Cdk5 in the treatment of neurodegenerative diseases. Since the identification of this unique member of the Cdk family, Cdk5 has emerged as one of the most important signal transduction mediators in the development, maintenance and fine-tuning of neuronal functions and networking. Further studies have revealed that Cdk5 is also associated with the regulation of neuronal survival during both developmental stages and in neurodegenerative diseases. These observations indicate that precise control of Cdk5 is essential for the regulation of neuronal survival. The pivotal role Cdk5 appears to play in both the regulation of neuronal survival and synaptic functions thus raises the interesting possibility that Cdk5 inhibitors may serve as therapeutic treatment for a number of neurodegenerative diseases.

Autoren/Hrsg.

Ip, Nancy Y.

Tsai, Li-Huei

Inhaltsverzeichnis

1;Preface;5
2;Contents;7
3;Contributors;9
4;About the Editors;15
5;Cdk5/p35 Regulates Neuronal Migration;17
5.1;Expression of Cdk5, p35, and p39 During Brain Development;17
5.2;Cdk5/p35 Deficiency Causes Neuronal Migration Defects in CNS;18
5.3;Normal Migration of Cortical Neurons and Alteration by Cdk5/ p35 Deficiency;19
5.4;Molecular Mechanism of the Regulatory Function of Cdk5/p35 in Neuronal Migration;20
5.5;Summary;22
5.6;References;22
6;CRMP Family Protein: Novel Targets for Cdk5 That Regulates Axon Guidance, Synapse Maturation, and Cell Migration;25
6.1;Introduction;26
6.2;Fyn and Cdk5 Are Involved in Sema3A Signaling;27
6.3;Plex-A2 Associates with Cdk5 via Interaction with Active Fyn, and Fyn Activates Cdk5 via Tyr15 Phosphorylation;28
6.4;Sema3A-Induced Growth Cone Collapse Is Mediated Through Cdk5 Activation via Tyr15 Phosphorylation;29
6.5;CRMP2 Is an In Vivo Substrate of Cdk5;30
6.6;Cdk5-Primed GSK3beta Phosphorylation of CRMP2;31
6.7;The Phosphorylation of CRMPs Disrupts Association of CRMPs with Tubulin;32
6.8;Sema3A-Induced Growth Cone Collapse Through Phosphorylation of CRMP2, and Evidence for Both CRMP1 and CRMP2 Are Involved in Sema3A Signaling;33
6.9;CRMP1 Regulates Spine Maturation Through Mediating Sema3A Signaling In Vivo;35
6.10;CRMP1 Mediates Reelin Signaling in Cortical Neuronal Migration;36
6.11;The Phosphorylation of CRMPs in Mediating Extacellular Signals;37
6.12;Conclusion;37
6.13;References;38
7;Cdk5 in Presynapses;41
7.1;Cdk5 in Presynapses;41
7.1.1;Cdk5 in Exocytosis;41
7.1.1.1;Cdk5 and Synapsin;42
7.1.1.2;Cdk5 and Munc-18;42
7.1.1.3;Cdk5 and Voltage-Gated Calcium Channels;43
7.1.1.4;Role of Cdk5 in Exocytosis;44
7.1.2;Cdk5 in Endocytosis;44
7.1.2.1;Cdk5 and Dynamin 1;44
7.1.2.2;Cdk5 and Amphiphysin;45
7.1.2.3;Cdk5 and Synaptojanin;46
7.2;Concluding Remarks;46
7.3;References;46
8;Cyclin-Dependent Kinase 5: A Critical Regulator of Neurotransmitter Release;50
8.1;Introduction;50
8.2;Effect of Cdk5 on the Exocytosis of Synaptic Vesicles in Presynaptic Terminals;53
8.2.1;Phosphorylation of Munc18-1 by Cdk5;54
8.2.2;Phosphorylation of Sept5 by Cdk5;55
8.2.3;Phosphorylation of Synapsin 1 by Cdk5;56
8.2.4;Phosphorylation of Pctaire1, a Kinase to Phosphorylate NSF by Cdk5;56
8.3;Effect of Cdk5 on Endocytosis in Presynaptic Terminals;57
8.3.1;Phosphorylation of Dynamin 1 by Cdk5;58
8.3.2;Phosphorylation of Amphiphysin I by Cdk5;58
8.3.3;Phosphorylation of Synaptojanin 1 by Cdk5;59
8.4;Effect of Cdk5 on Neurotransmitter Synthesis;59
8.4.1;Phosphorylation of Tyrosine Hydroxylase by Cdk5;59
8.5;Control of Presynaptic Ca and Lipid Signaling by Cdk5;60
8.5.1;Phosphorylation of P/Q-Type Calcium Channels by Cdk5;60
8.5.2;Phosphorylation of PIPKIgamma by Cdk5;61
8.6;Conclusion;61
8.7;References;62
9;Cdk5 in Dendrite and Synapse Development: Emerging Role as a Modulator of Receptor Tyrosine Kinase Signaling;66
9.1;Dendrite, Spine, and Synapse Development;66
9.2;Cdk5: an Atypical Cyclin-Dependent Kinase;68
9.3;Regulation of Dendrite Development by Cdk5;68
9.3.1;Cdk5 as a Modulator of Extracellular Cues;69
9.3.1.1;Neurotrophins;69
9.3.1.2;Semaphorin 3A;71
9.3.2;Cdk5: Regulator of Cytoskeletal Components;72
9.3.2.1;Regulation of Actin Dynamics Through Modulation of Rho GTPases;72
9.3.2.2;Regulation of Microtubule Dynamics;73
9.4;Regulation of Synapse Formation by Cdk5;73
9.4.1;Regulation of Neurotransmitter Receptor Expression;75
9.4.1.1;Cdk5 as a Modulator of Extracellular Cues Signaling;75
9.4.1.2;Regulation of Gene Transcription Machinery by Cdk5;75
9.4.2;Regulation of Neurotransmitter Receptor Clustering;76
9.5;Regulation of Spine Development;76
9.5.1;Regulation of Spine Morphology Through Modulation of Extracellular Cues and Rho GTPase;77
9.5.2;Regulation of Spine Morphology Through Modulating Synaptic Activity;77
9.6;Cdk5: Modulator of RTK Signaling;78
9.7;References;80
10;Cyclin-Dependent Kinase 5 (Cdk5) Modulates Signal Transduction Pathways Regulating Neuronal Survival;84
10.1;Introduction;84
10.2;Cdk5-MAPK Cross Talk;87
10.2.1;Inhibition of Cdk5 Activity Induces Neuronal Apoptosis by Increased and Sustained Erk1/2 Activation;91
10.3;Cdk5-JNK3 Cross Talk;92
10.3.1;Cdk5 Phosphorylates JNK3;92
10.3.2;Cdk5 Phosphorylation of JNK3 Inhibits c-Jun Phosphorylation;94
10.4;Cdk5-Receptor Tyrosine Kinase (Erb2/3) Cross Talk;95
10.5;Other Signaling Pathways Regulated by Cdk5;98
10.5.1;Cdk5 and GSK3 Cross Talk Affects Fast Axonal Transport;98
10.5.2;Cdk5-RasGRF Cross Talk, Upstream of the MAPK Pathway;99
10.6;Concluding Remarks;100
10.7;References;102
11;CDK5 and Mitochondrial Cell Death Pathways;106
11.1;Programmed Cell Death;106
11.2;Apoptosis in Neuronal Cells;107
11.3;Mitochondrial Apoptosis Pathways and CDK5 Toxicity;108
11.4;Dynamics of Mitochondrial Morphology;110
11.5;The Mitochondrial Fission Machinery;111
11.6;The Mitochondrial Fusion Machinery;112
11.7;Mitochondrial Morphology During Neuronal Apoptosis;113
11.8;Regulation of Mitochondrial Fission by CDK5;115
11.9;Mitochondrial CDK5 Substrates;117
11.10;Summary;117
11.11;References;118
12;Regulation and Function of Cdk5 in the Nucleus;122
12.1;Introduction;122
12.2;Detection of Cdk5 and Its Activators in the Nucleus;123
12.3;Nuclear Function of Cdk5 and p35;124
12.3.1;Nuclear Transcription Factors Targeted by Cdk5;125
12.3.2;Non-Transcription Factor Targets of Cdk5 in the Nucleus;128
12.4;Regulation of Nuclear Cdk5 and Its Activators;129
12.4.1;Regulation of the Level and Nuclear Localization of p35 and p25;129
12.4.2;Association of Cdk5 with Cyclins;130
12.5;Final Remarks;131
12.6;References;131
13;Cdk5 May Be an Atypical Kinase, but Not in the Way You Think;134
13.1;Introduction;134
13.1.1;The Cyclin-Dependent Kinase Family;134
13.1.2;Cyclin-Dependent Kinases and Normal Cell Cycle Regulation;135
13.1.3;Regulation of Cyclin-Dependent Kinases;136
13.2;Cell Cycle Regulation in Post-Mitotic Neurons;137
13.2.1;Development and In Vitro Systems;137
13.2.2;Aberrant Cell Cycle Events in Neurodegenerative Diseases;138
13.2.3;Cell Cycle Events in Mouse Disease Models;139
13.3;Cdk5: An Atypical CDK;140
13.3.1;The Regulation of Cdk5;140
13.4;Function of Cdk5;141
13.4.1;The Roles of Cdk5 in the Adult;141
13.4.1.1;Synapse Function;141
13.4.1.2;Neuronal Survival;141
13.4.2;The Roles of Cdk5 in Development;142
13.4.2.1;Migration;142
13.4.2.2;Survival;142
13.5;Cdk5 and the Cell Cycle Regulation in Neurons;143
13.6;Conclusion and Perspectives;146
13.7;References;147
14;Cdk5 and Neuregulin-1 Signaling;153
14.1;References;157
15;Cyclin-Dependent Kinase 5 and Insulin Secretion;159
15.1;Glucose Stimulation/Insulin Secretion Coupling in the Pancreatic beta-Cell;160
15.2;Regulated Exocytosis of Insulin;161
15.3;Cdk5 in Pancreatic beta-Cells;163
15.4;Cdk5/p39 in Insulin Exocytosis and beta-cell Physiology;165
15.5;Is Cdk5 Positively or Negatively Regulating Insulin Secretion?;167
15.6;References;169
16;Protein-Protein Interactions Involving the N-Terminus of p35;173
16.1;Introduction;173
16.2;N-Terminus of p35 Interacts with Various Proteins;174
16.3;Regulation of Cdk5 Activation;175
16.4;Nuclear Import of p35;176
16.5;Cdk5-p35 in the Control of S6 Kinase 1 Activation;178
16.6;Regulation of Microtubule Organization;179
16.7;Conclusion;182
16.8;References;182
17;The Kinase Activity of Cdk5 and Its Regulation;185
17.1;Introduction;185
17.2;Kinase Properties of Cdk5;186
17.2.1;Cdk5 Activated by p35 or its N-Terminal Truncated Form p25;186
17.2.2;Cdk5 Activated by p39;189
17.2.3;Effects of the N-terminal p10 Domain on the Kinase Activity of Cdk5;191
17.3;Regulation of Cdk5 Activity;193
17.3.1;Considerations from the Activation Mechanisms of Cdk1-Cyclin B in Proliferating Cells;193
17.3.2;Regulation of Cdk5 Activity by Synthesis and Degradation of p35;195
17.3.3;Regulation of Cdk5 Activity by Phosphorylation;197
17.3.4;Protein Modulators of Cdk5 Activity;198
17.3.5;Suppression of the Cdk5 Activity by Membranes;198
17.4;Summary;199
17.5;References;199
18;The Structural Bases of CDK5 Activity;205
18.1;Introduction;205
18.2;Regulation of Protein Kinases: General Remarks;206
18.3;Structure of the ePK Catalytic Domain;207
18.4;Conformational Regulation of Kinase Activity;211
18.5;CDK5: Structural Considerations;213
18.6;The Inhibition of CDK5;216
18.7;The Substrate Specificity of CDK5;217
18.8;Web Resources;219
18.9;References;219
19;Cdk5, a Journey from Brain to Pain: Lessons from Gene Targeting;225
19.1;Cdk5 Knockout (Cdk5-/-) Mice;226
19.2;Cdk5 Chimeric Mice (Cdk5-/- lrarrCdk5plus1/plus1);227
19.3;Cdk5 Overexpressing Transgenic (TgCdk5) Mice;228
19.4;Cdk5 Overexpression Under the Control of p35 Promoter in Cdk5-null (TgKO) Mice;228
19.5;p35 Knockout (p35-/-) Mice;229
19.6;p35 Knockout and Cdk5 Heterozygous Mice (p35-/-; Cdk5plus1/-);230
19.7;p35 Overexpressing Transgenic (Tgp35) Mice;230
19.8;p35 Overexpression Under a p35 Promoter in p35-null (Tgp35;p35-/-) Mice;230
19.9;p25 Expressing Transgenic (p25-tg) Mice;231
19.10;Inducible Transgenic Mice Overexpressing p25 in the Postnatal Forebrain;231
19.11;Low Expression of the p25 Transgene Under the NSE Promoter in p35-null (p35-/-;p25-tg) Mice;232
19.12;p39 Knockout (p39-/-) Mice;233
19.13;p35 and p39 Double Knockout (p35-/-;p39-/-) Mice;233
19.14;Cdk5 Floxed (Cdk5f/f) Mice;234
19.15;Cdk5 and Pain;235
19.16;References;238
20;Involvement of Cdk5 in Synaptic Plasticity, and Learning and Memory;241
20.1;Introduction;241
20.2;Molecular Mechanisms of Synaptic Plasticity;242
20.2.1;Pre-synaptic Mechanisms;247
20.2.2;Post-synaptic Mechanisms;252
20.2.3;Extra-Synaptic Mechanisms;255
20.3;Cdk5 in Cellular Mechanisms of Synaptic Plasticity;256
20.3.1;Short-Term Plasticity;258
20.3.2;Long-Term Plasticity;259
20.4;Cdk5 in Learning and Memory;262
20.5;Putative Mechanisms Underlying Cdk5-Mediated Effects in Synaptic Plasticity, and Learning and Memory;265
20.6;Conclusion;266
20.7;References;267
21;Cyclin-Dependent Kinase 5 (Cdk5): Linking Synaptic Plasticity and Neurodegeneration;275
21.1;Synaptic Plasticity, Learning, and Memory;275
21.2;Cdk5 is a Novel Regulator of Synaptic Plasticity;277
21.3;Deregulated Cdk5 Activity is Implicated in Neurodegenerative Diseases;282
21.4;p25 as a Plasticity Factor;286
21.5;References;289
22;Cdk5 as a Drug Target for Alzheimer’s Disease;297
22.1;Introduction;297
22.2;CDK5 in Tau Hyperphosphorylation;299
22.3;Beyond Tau Hyperphosphorylation;301
22.4;Safety of Cdk5 Inhibitors;303
22.5;References;306
23;Index;314