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Kinomics: Approaches and Applications

Kinomics: Approaches and Applications

Heinz-Bernhard Kraatz (Editor), Sanela Martic (Editor)

ISBN: 978-3-527-33765-1

Nov 2015

368 pages

In Stock

$190.00

Description

Authored by the world's leading kinase experts, this is a comprehensive introduction to current knowledge and practice within this emerging field.
Following an overview of the major players and pathways that define the kinome, the major part of this work is devoted to current strategies of kinome investigation and manipulation. As such, kinase engineering, peptide substrate engineering, co-substrate design and kinase inhibitor design are discussed in detail, and their potential applications in kinome analysis and kinome-based pharmacotherapy are shown.
The result is a toolbox for every kinase researcher: By addressing and comparing current approaches to the study of kinase action, both novice and established researchers will benefit from the practical knowledge contained in this invaluable reference.

List of Contributors XIII

Preface XIX

Part I Protein Kinases Cell Signaling 1

1 Global Approaches to Understanding Protein Kinase Functions 3
Jennifer L. Gorman and James R.Woodgett

1.1 A Brief History of the Structure of the Human Kinome 3

1.1.1 AGC Kinases 3

1.1.2 The CaMK Family 5

1.1.3 CMGC Family Kinases 5

1.1.4 STE Family Kinases 7

1.1.5 Tyrosine Kinases 7

1.1.6 Casein Kinases 8

1.1.7 Tyrosine Kinase-Like Family 9

1.1.8 RGC Kinases 9

1.1.9 Atypical/Other Protein Kinases 9

1.2 Why Study Protein Kinases – Their Roles in Disease 10

1.2.1 Neurodegenerative Disease 10

1.2.2 Hallmarks of Cancer 13

1.3 Methodology for Assessment of Protein Kinase Functions 16

1.3.1 Mass Spectrometry 16

1.3.2 Fluorescence Resonance Energy Transfer 18

1.3.3 Assessment of Kinase Functions in vitro: Genetic and Chemical 20

1.3.4 Functional Assessment of Kinase Function in vivo: Animal Models 22

1.3.5 CRISPR/Cas9 Genomic Recombineering 25

1.4 FinalThoughts 28

Acknowledgments 29

References 29

2 “Genuine” Casein Kinase (Fam20C): TheMother of the Phosphosecretome 47
Giorgio Cozza, Vincent S. Tagliabracci, Jack E. Dixon, and Lorenzo A. Pinna

2.1 Introduction 47

2.2 Early Detection of the pS-x-E Motif in Secreted Phosphoproteins 48

2.3 CK1 and CK2 are Not Genuine Casein Kinases 50

2.4 Polo-Like Kinases: Newcomers in the Club of False “Casein Kinases” 51

2.5 Characterization of an Orphan Enzyme: The Spectacular Performance of a Peptide Substrate 51

2.6 Catalytic Activity of Fam20C: Mechanistic Aspects 53

2.7 A Kinase in Need of Control 54

2.7.1 Constitutively Active or Inactive? 54

2.7.2 A Potential Mediator of Sphingosine Signaling 55

2.7.3 Fam20c as a Novel Regulator of Blood Phosphate Homeostasis 56

2.7.4 Does it Make Sense to Develop Fam20C Inhibitors? 56

2.8 Outlook 57

Funding 58

References 58

3 Chemical Biology of Protein Kinases 63
David Mann

3.1 The Basis of Chemical Genetics 63

3.2 Protein Kinase Chemical Genetics 65

3.3 Applications for AS Kinases 68

3.3.1 Substrate Identification: General Phosphoproteomics 69

3.3.2 Substrate Identification: Refinements through the Use of AS Kinases 70

3.3.3 Substrate Identification in Action: What HaveWe Learned? 73

3.3.4 Use of Specific Inhibitors for AS Kinases 75

3.4 Current Challenges 77

3.5 Conclusions 80

Acknowledgments 81

References 81

4 Protein Kinases and Caspases: Bidirectional Interactions in Apoptosis 85
Stephanie A. Zukowski and David W. Litchfield

4.1 Introduction 85

4.2 Apoptosis: Caspase-Dependent Pathways 86

4.2.1 Extrinsic Apoptosis 86

4.2.2 Caspase-Dependent Intrinsic Apoptosis 87

4.3 Functional Crosstalk between Protein Kinases and Caspases 88

4.3.1 Direct Phosphorylation of Caspases by Protein Kinases 89

4.3.1.1 Initiator Caspases 89

4.3.1.2 Executioner Caspases 91

4.3.2 Cleavage of Caspase Substrates is Positively and Negatively Regulated by Protein Kinase Phosphorylation 91

4.3.3 Caspase-Mediated Degradation of Kinases and Apoptotic Progression 94

4.3.3.1 Rho-Associated Coiled-Coil-Containing Protein 1 (ROCK1) 94

4.3.3.2 p21-Activated Protein Kinase 2 (PAK2) 96

4.3.3.3 Focal Adhesion Kinase (FAK) 97

4.3.3.4 Protein Kinase Akt 97

4.3.3.5 Protein Kinase Cδ (PKCδ) 97

4.4 Strategies to Investigate Global Crosstalk between Protein Kinases and Caspases 99

4.4.1 Computational Approaches and Bioinformatics: Investigating Overlap between Protein Kinase Consensus Sites and Caspase Recognition Motifs 99

4.4.2 Proteomics-Based Strategies to Investigate Crosstalk within the Phosphoproteome and the Caspase Degradome 101

4.4.3 Reporters to Monitor the Spatial and Temporal Dynamics of Phosphorylation and Caspase Cleavage in Living Cells 103

4.5 Implications and Future Prospects 103

References 104

5 The Kinomics of Malaria 115
Mathieu Brochet, Andrew B. Tobin, Oliver Billker, and Christian Doerig

5.1 Introduction 115

5.1.1 Malaria Parasites: Highly Divergent Eukaryotes 115

5.1.2 Posttranslational Modifications of Proteins: An Essential Multiplier of Proteome Complexity 116

5.2 The Plasmodium Kinome: Salient Features 117

5.3 Reverse Genetics of the Plasmodium Kinome 120

5.4 Lessons from Phosphoproteomics 123

5.4.1 Phosphorylation Cascades 124

5.4.2 Evidence for Tyrosine Phosphorylation Plasmodium 124

5.5 Host Cell Kinomics in Malaria Infection 127

5.6 Targeting Protein Kinases in Antimalarial Drug Discovery 128

5.6.1 Targeting the Parasite Kinome for Curative and Transmission-Blocking Intervention 128

5.6.2 Targeting Host Kinases? 129

5.7 Concluding Remarks 130

References 130

Part II ATP Co-substrate Design 137

6 ATP Analogs in Protein Kinase Research 139
Thilani M. Anthony, Pavithra M. Dedigama-Arachchige, D. Maheeka Embogama, Todd R. Faner, Ahmed E. Fouda, and Mary Kay H. Pflum

6.1 Base-Modified ATP Analogs 140

6.1.1 C2, C6, and C8-Modified ATP Analogs 141

6.1.2 N6-Modified ATP Analogs 141

6.1.2.1 Gatekeeper as-Kinase Mutants 143

6.1.2.2 Multiply Mutated as-Kinases 144

6.1.3 Pyrazolopyrimidine ATP Analogs 145

6.1.4 Triazole and Imidazole ATP Analogs 146

6.1.5 Applications of as-Kinases and Base-Modified ATP Analogs 147

6.2 Sugar-Modified ATP Analogs 148

6.3 α- and β-Phosphate-Modified ATP Analogs 149

6.3.1 AMP-PCP 150

6.3.2 AMP-PNP 151

6.3.3 AMP-CPP 151

6.4 γ-Phosphate-Modified ATP Analogs 152

6.4.1 ATPγS 153

6.4.2 ATP-Biotin 155

6.4.3 ATP-Fluorophore Analogs 157

6.4.4 ATP-Ferrocene 158

6.4.5 ATP-Arylazide and ATP-Benzophenone 158

6.4.6 γ-Alkenyl-, γ-Alkynyl-, γ-Azido-ATP 159

6.4.7 Bifunctional C8-Azido- and γ-Arylazido-ATP 160

6.4.8 ATP-Acyl-Biotin 160

6.5 Conclusions 161

References 163

7 Electrochemical Detection of Protein Kinase-Catalyzed Phosphorylations 169
Sanela Martic, Soha Ahmadi, Zhe She, and Heinz-Bernhard Kraatz

7.1 Introduction 169

7.1.1 Label-Free Detection of Phosphorylation 169

7.1.1.1 Gold NPs 169

7.1.1.2 Silver Nanoparticles (AgNPs) 173

7.1.1.3 Solution-Based Redox Probes 173

7.1.2 Labeled Detection of Phosphorylation 175

7.1.2.1 Ferrocene–ATP Cosubstrate 175

7.1.2.2 Probing Protein Kinase Binding Pocket 177

7.1.2.3 Probing Phosphoprotein Binding 181

7.1.2.4 Probing Phosphoprotein Conformational Change 182

7.1.2.5 Detection of Protein Kinase Inhibitors 183

7.1.2.6 Utility of Fc–ATP Beyond Electrochemistry 187

7.2 Conclusions 187

References 190

Part III New Methodologies for Kinomics 193

8 Phos-tag Technology for Kinomics 195
Emiko Kinoshita-Kikuta, Eiji Kinoshita, and Tohru Koike

8.1 Introduction 195

8.2 Kinomics and Phosphoproteomics 196

8.3 Phos-tag Technology 196

8.4 Highly Sensitive Detection of Phosphopeptides and Phosphoproteins by the Phos-tag Biotin Method 197

8.4.1 Outline 197

8.4.2 Application of Phos-tag Biotin in Peptide Microarrays 197

8.4.3 Application of Phos-tag Biotin inWestern Blotting 200

8.5 Protein Kinase Assay with Phos-tag Sodium Dodecyl Sulfate-Polyacrylamide Gel Electrophoresis 201

8.5.1 Outline 201

8.5.2 Quantitative Analysis of Abl Tyrosine Kinase Activity 202

8.5.3 Simultaneous Detection of the Activation/Inactivation of Extracellular Signal-Regulated Kinases 204

8.5.4 Differential Analysis of the Phosphorylation Statuses of Cellular Proteins in Combination with Two-Dimensional Difference Gel Electrophoresis 206

8.6 Conclusion 208

References 208

9 Development of Species- and Process-Specific Peptide Kinome Arrays with Priority Application to Investigations of Infectious Disease 211
Ryan Arsenault, Brett Trost, Anthony Kusalik, and Scott Napper

9.1 Phosphorylation-Mediated Signal Transduction 211

9.1.1 Kinome versus Phosphoproteome Analysis 212

9.2 Peptide Arrays for Kinome Analysis 213

9.2.1 Species-Specific Peptide Arrays for Kinome Analysis 214

9.2.2 Analysis of Data from Kinome Microarrays 217

9.3 Infectious Disease 218

9.3.1 Human Infectious Agents 220

9.3.1.1 Monkey Pox 220

9.3.1.2 Prion Disease 221

9.3.2 Livestock Pathogens 222

9.3.2.1 Cattle 222

9.3.3 Application of Arrays to Samples of Greater Biological Complexity 225

9.3.3.1 Kinome Profiling of MAP-Infected Calf Intestinal Tissues 226

9.3.3.2 Poultry 226

9.3.3.3 Honeybees and Colony Collapse Disorder (CCD) 227

9.4 Conclusions 228

References 229

10 New Approaches to Understanding Bacterial Histidine Kinase Activity and Inhibition 233
Kaelyn E.Wilke and Erin E. Carlson

10.1 Introduction to Two-Component System Signaling 233

10.2 Focus on Bacterial HKs 235

10.3 Bacterial HK Activity 235

10.3.1 Significance of Understanding HK Activity 235

10.3.1.1 Detection of HK Activity:The Major Obstacle 236

10.3.2 Current Methods for Studying HK (and TCS) Activity 237

10.3.2.1 Genetic Characterization 237

10.3.2.2 Elucidation of TCS Activity at the Protein Level 237

10.3.3 Thiophosphorylation as a Stable Alternative 238

10.3.4 BODIPY-FL-ATPγS Probe 239

10.3.5 Future Challenges and Developments 240

10.4 Bacterial HK Inhibition 242

10.4.1 Significance 242

10.4.2 HK Inhibitors: Past and Present 242

10.4.3 Repurposing Unsuccessful Inhibitors 245

10.4.4 Future HK Inhibitor Developments 248

10.5 Outlook on Tools for the Study and Inhibition of Bacterial HKs 248

References 248

11 Methods for Large-Scale Identification of Protein Kinase Substrate Networks 255
KassaDee J. Ketelaar and Ian S.Wallace

11.1 Introduction 255

11.2 Computational Prediction of Phosphorylation Sites and Protein Kinase–Substrate Relationships 256

11.3 The Role of Mass Spectrometry in Identifying Posttranslational Modifications 259

11.4 Analog-Sensitive Kinases and Other Specific Inhibitors 264

11.5 Array-Based Methods 266

11.6 Solution-Based Methods 269

11.7 Future Perspectives 271

References 272

Part IV Kinase Inhibition 281

12 Developing Inhibitors of STAT3: Targeting Downstream of the Kinases for Treating Disease 283
Andrew M. Lewis, Daniel P. Ball, Rahul Rana, Ji Sung Park, David Rosa, Ping-Shan Lai, Rodolfo F. Gómez-Biagi, and Patrick T. Gunning

12.1 Introduction 283

12.2 STAT3 Structure and Signaling 284

12.2.1 The Role of STAT3 in Cancer 287

12.2.2 STAT3 in Inflammatory Disease 287

12.2.3 STAT3 in Alzheimer’s Disease 287

12.3 Methods for Directly Inhibiting STAT3 288

12.3.1 Peptide Inhibitors of STAT3 288

12.3.2 Small-Molecule Inhibitors of STAT3 290

12.3.2.1 Inhibitors of the SH2 Domain 290

12.3.2.2 Natural Product Inhibitors of STAT3 294

12.3.3 Oligonucleotide Decoys of STAT3 Transcription 296

12.4 Conclusion 296

References 298

13 Metal Compounds as Kinase and Phosphatase Inhibitors in Drug Development: The Role of the Metal and Ligands 301
Maria V. Babak, Margaux Airey, and Christian G. Hartinger

13.1 Introduction 301

13.2 Kinase Inhibitors: From Ideal 3D Shapes to Kinase Inhibitor-Derived Ligands in Metal Complexes 302

13.2.1 Metal-Based Kinase Inhibitors: Taking Advantage of the Unique 3D Structure of Metal Complexes 302

13.2.2 Non-ATP Binding Site Targeting Kinase Inhibitors 309

13.2.3 Metal-Based Paullones, Indoloquinolines, and Quinoxalinones: Coordination of Bioactive Ligands to Metal Centers 311

13.2.4 Flavonol- and Hydroxypyridone-Derived Complexes: Toward Multimodal Anticancer Agents 317

13.2.5 Exploiting Metal Compounds for Selective Activation and Targeted Release of Kinase Inhibitors 318

13.3 Phosphatases and Metal Compounds 319

13.3.1 Therapeutic Potential of Metal-Based PTP Inhibitors 319

13.3.2 Inorganic Vanadium Salts as Reversible and Irreversible PTP Inhibitors 320

13.3.3 Vanadium Coordination Compounds as Phosphatase Inhibitors 322

13.4 Conclusions 323

Acknowledgments 323

References 324

Index 331