| Preface | ix |
1. | Introduction | 1 |
| The Protein Phosphorylation Reaction | 1 |
| Protein Kinases | 1 |
| Protein Kinase C | 2 |
| Protein Kinase C Isotypes and Their Domain Structure | 2 |
| Defining the PKC Family | 4 |
| This Book | 5 |
2. | Structure, Function and Membrane Interactions of C1 Domains | 8 |
| C1 Domain Structure and Stereospecific Ligand Recognition | 9 |
| Membrane Binding and Subcellular Localization of C1 Domains | 11 |
| Typical C1 Domains in Proteins Other than PKC | 12 |
| Atypical C1 Domains | 12 |
| C1 Domains in the Context of Multidomain Signaling Proteins | 13 |
3. | Structural and Functional Specialization of C2 Domains in Protein Kinase C | 16 |
| C2 Domain Structure | 17 |
| C2 Domain Interactions with Ligands | 20 |
| Mechanism of Membrane Targeting of PKC by C2 Domains | 25 |
4. | Regulation of Protein Kinase C by Membrane Interactions | 36 |
| Protein Kinase C: At the Heart of Lipid Signalling | 36 |
| The Three Cofactors: Phosphatidylserine, Diacylglycerol, and Ca[superscript 2+] | 37 |
| Translocation of Protein Kinase C | 42 |
| Phosphorylation: Regulator of Protein Kinase C's Subcellular Location | 44 |
5. | Protein Kinase C Regulation by Protein Interactions | 49 |
| Examples of PKC Binding Proteins | 51 |
| Discussion | 59 |
6. | Regulation of Protein Kinase C by Phosphorylation | 63 |
| Phosphorylation at the Activation Loop | 64 |
| Phosphorylation at the Turn Motif | 67 |
| Phosphorylation at the Hydrophobic Site | 68 |
| The Role of the Phosphoinositide 3-Kinase Pathway | 69 |
| Regulation by Dephosphorylation | 70 |
| Implications for Cellular Function | 71 |
| Regulation of Protein Kinase C by Tyrosine Phosphorylation | 71 |
7. | Down-Regulation of Protein Kinase C | 76 |
| The Proteolytic Mechanism | 78 |
| Role of Down-Regulation | 82 |
8. | Protein Kinase C in Yeast: The Cell Wall Integrity Pathway | 87 |
| Yeasts PKC Homologues | 87 |
| Rho GTPases and PKC Activation | 88 |
| S. cerevisiae Pkc1p and the Cell Integrity Pathway | 90 |
| Cell Integrity Pathway and Cell Cycle | 91 |
| Interaction with Other Pathways | 93 |
| Function of Pck1p and Pck2p in S. pombe Cell Integrity and Cell Wall Biosynthesis | 93 |
9. | Specificity in Atypical Protein Kinase C Signaling: The NF-[kappa]B Paradigm | 100 |
| The NF-[kappa]B Pathway | 100 |
| Adapters for the aPKCs to NF-[kappa]B Activation | 103 |
| Functional Relevance of the aPKCs in the Ras-NF-[kappa]B Crossroad | 106 |
| Specificity during Cell Signaling | 106 |
| Blockade of NF-[kappa]B by the Endogenous aPKC Inhibitor Par-4 | 109 |
10. | Protein Kinase C: A Molecular Information Storage Device in Neurons | 114 |
| Activity-Dependent Synaptic Plasticity | 114 |
| Inhibitors of PKC Block LTP | 116 |
| Activating PKC Mimics LTP | 117 |
| Biochemical Studies | 118 |
| Oxidative Modification of PKC | 118 |
| Protein Kinase Substrates Phosphorylated during LTP | 119 |
| Cerebellar Long-Term Depression | 121 |
| PKC in Learning and Memory | 121 |
| Changes in Activity, Cellular Distribution and Phosphorylation of Substrates | 122 |
| Pharmacological Inhibition of PKC | 123 |
| Isotype Specific PKC Knockout | 123 |
11. | Involvement of PKC in the Sensation of Pain | 134 |
| Role of PKC in Peripheral Nociception | 136 |
| Sensitization of the Heat-Gated Current by PKC | 136 |
| Desensitization of VR1 by Calcineurin | 138 |
| Phosphorylation of VR1 | 138 |
| PKC Isotypes Involved in VR1 Phosphorylation | 139 |
| PKC-[varepsilon] and Inflammatory Pain | 139 |
| Actions of PKC on Voltage-Sensitive Na Currents | 140 |
| Specific Involvement of PKC-[varepsilon] in Neuropathic Pain | 141 |
| Conclusion: Peripheral Nociception | 141 |
| Involvement of PKC in Central Pain Processing | 141 |
| Protein Kinase C-[gamma] and Persistent Pain | 142 |
| PKC Activity, Opioid Tolerance and Pathological Pain States Are Related | 142 |
12. | The Protein Kinase C Gene Module: Cellular Functions in T Lymphocytes | 147 |
| The PKC Kinases: A Gene Family of Nine Isotypes | 147 |
| Regulation of PKC Activity in T Cells | 149 |
| Signaling Specificity of PKC in T Cells--A Complex Affair | 150 |
| Role of PKC in T Lymphocyte Physiology | 153 |
| PKC and T Cell Activation | 153 |
| T Cell Antigen Receptor | 153 |
| Integrin Receptors | 155 |
| Cytokine Receptors | 156 |
| Are There any Other Critical Pathways Modulated by PKC | 157 |
| Role of PKC in Lymphocyte Development | 157 |
| Role of PKC in Lymphocyte Homeostasis | 158 |
| PKCs in Lymphocyte Disorders | 159 |
| Synopsis and Future Perspectives | 159 |
13. | Protein Kinase C Isotype Function in Neutrophils | 165 |
| Basic Cell Biological Properties of Neutrophils | 165 |
| PKC Isotypes in Neutrophils | 168 |
| Studying PKC Isotype Function in Neutrophils | 171 |
| Molecular Targets of PKC in Neutrophils | 173 |
| Index | 191 |