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Protein Kinase CK2

Lorenzo A. Pinna

ISBN: 978-1-118-48234-6 October 2012 Wiley-Blackwell 480 Pages


Protein kinases play a critical role in cellular processes that impact overall organismal health and function. Of the kinases that collectively make up the Human Kinome, CK2 has garnered special attention because of its significant role in the generation of the human phosphoproteome. The role CK2 plays in the development of cancer and other disease has also made it of significant interest for its potential role in future therapeutics. Protein Kinase CK2 comprehensively brings together the varied work being done on this critical enzyme.

Protein Kinase CK2 is logically divided into three sections. The first section reviews key molecular and structural aspects of the enzyme. The second section looks at functional aspects of CK2 and the diverse roles it plays in cellular development, function, and health. The final section focuses on CK2 and cancer, looking at the impacts of the kinase on neoplastic development and its rapidly developing role as a therapeutic agent.

With contributions from the world’s leading experts in the field, Protein Kinase CK2 will serve as an invaluable guide to the expanding and vibrant body of research being performed on this enzyme. This will be an essential volume for anyone working in the fields of biochemistry, protein science, signal transduction, metabolic regulation, and cancer biology and therapeutics.

Lorenzo A. Pinna is Professor in the Department of Biomedical Sciences at the University of Padua, Padua, Italy.

Also Published in the Wiley-IUBMB Series on Biochemistry and Molecular Biology:

Plant Phenolics and Human Health: Biochemistry, Nutrition, and Pharmacology
Edited by Cesar G. Fraga
ISBN: 978-0-470-28721-7

Contributors xi

Preface xv

Part 1 Molecular and Structural Aspects 1

1 Structural Bases of Protein Kinase CK2 Function and Inhibition 3
Karsten Niefind and Roberto Battistutta

Introduction 3

Basic Structure/Function Relationships of CK2 8

CK2 Inhibitors 37

Conclusions and Outlook 60

Acknowledgments 61

2 The Interactome of Protein Kinase CK2 76
Mathias Montenarh and Claudia Götz

Introduction 76

From the Outside to the Inside: Interaction of CK2 with Membrane Proteins 78

Regulating Gene Expression: Interaction of CK2 with Components of Signaling Cascades, Transcription Factors and DNA Modifying Enzymes 82

Mastering Nucleic Acid Functions: Interaction of CK2 with Proteins of the Replication, Transcription, and Translation Machinery of the Cell 87

Let It Roll: Interaction of CK2 with Cell Cycle Regulatory Proteins 90

Guardian Angels: Interaction of CK2 with Proteins That Maintain the Cellular Integrity 93

Live and Let Die: Interaction of CK2 with Proteins of the Apoptotic Pathway 96

Highways in the Cell: Interaction of CK2 with the Cytoskeleton and Motor Proteins 96

Collaborating with the Enemy: Interaction of CK2 with Proteins Implicated in Viral Infections 98

Last But Not Least: Miscellaneous 99

Concluding Remarks 101

3 CK2 Contribution to the Generation of the Human Phosphoproteome 117
Luca Cesaro and Mauro Salvi

Kinases Contribution to the Human Phosphoproteome 117

CK2 Substrate Specificity 118

Subphosphoproteomes of Proteins with Specific Functions 122

Subphosphoproteomes of Cellular Compartments 123

Absolute Quantification of Yeast Phosphoproteome Reflects the Constitutive Activity of CK2 125

Conclusions 125

Acknowledgments 126

Part 2 Functional Aspects 129

4 CK2 in Embryonic Development 131
Laura Macias Alvarez, Jesus Revuelta-Cervantes, and Isabel Dominguez

CK2 in Yeast Biology 131

CK2 in Invertebrate Development 135

CK2 in Vertebrate Development 139

CK2 in Plant Development 148

CK2 in Animal Developmental Signaling Pathways 149

Discussion 155

Outlook 157

Acknowledgments 158

5 Protein Kinase CK2: At the Crossroads of Pathways Controlling Cell Proliferation and Survival 169
Michelle Gabriel and David W. Litchfield

General Introduction 169

Protein Kinase CK2 170

CK2 in Cancer 171

Involvement of CK2 in Signaling Pathways Controlling Proliferation and Death 172

Concluding Remarks 182

Acknowledgments 183

6 The Role of Protein Kinase CK2 in the p53 Response 190
David W. Meek

Protein Kinase CK2 190

The p53 Network 191

The Interaction Between p53 and CK2 192

Regulation of p53 by Phosphorylation of Ser392 193

Proposed Mechanism for Regulation of p53 Phosphorylation at Ser392 (the “CK2” Site) 194

Phosphorylation of p53 by CK2 in a Physiological Context? 196

A Broader Role for CK2 in Regulating the p53 Network? 197

7 The Pivotal Role of CK2 in the Kinome-Targeting Hsp90 Chaperone Machinery 205
Yoshihiko Miyata

Protein Kinase CK2 205

Hsp90: A Major Molecular Chaperone 206

Co-Chaperones That Regulate Hsp90 Function 208

Hsp90 and Signaling Protein Kinases 212

Phosphorylation and the Regulation of Hsp90 by CK2 217

Phosphorylation of Cdc37 by CK2 218

A Crucial Role of CK2-Dependent Phosphorylation in the Functional Regulation of Cdc37 220

Regulation of the Cdc37 Phosphorylation Cycle 220

Regulatory Phosphorylation of FKBP52 by CK2 223

Phosphorylation of p23 by CK2 224

Targeting the CK2-Cdc37-Hsp90 Trinity for Cancer Chemotherapy 224

Conclusion 227

8 CK2: A Global Regulator of Cell Survival 239
Barbara Guerra and Olaf-Georg Issinger

CK2 and Cell Survival: Strategies, Methods, and Techniques for Exploring Its Role 239

CK2 and Cellular Death 244

Role of CK2 in DNA Damage 246

Role of the Individual CK2 Subunits in Cell Survival 248

CK2 Status in Non-neoplastic Cells 250

CK2 Activity and Expression in Neoplasia 252

CK2 in Heterotransplanted Tumors in Nude Mice 252

CK2 Holoenzyme and Its Subunits 253

Tumor Hypoxia 255

Conclusion 257

9 Specific Features of Plant CK2 267
Marta Riera, Isabel Cristina Vélez-Bermúdez, Tommaso Legnaioli, and Montserrat Pagès

Introduction 267

CK2α Catalytic Subunits 268

CK2β Regulatory Subunits 274

CK2 Holoenzyme 276

Physiological Role of CK2 in Plants 279

Part 3 Ck2 And Neoplasia 291

10 The Oncogenic Potential of CK2 293
David C. Seldin and Esther Landesman-Bollag

Introduction 293

CK2 Overexpression in Human Cancer 294

CK2 Is Overexpressed in Animal Models of Cancer 297

CK2 Overexpression in Transgenic Mice Leads to Cancer 297

Possible Targets of CK2 in Cancer: Wnt, NF-κB, and PI3-Kinase Pathways 298

Conclusions 301

Acknowledgments 301

11 Addiction of Cancer Cells to CK2: Survival at All Costs or Achilles’ Heel? 305
Maria Ruzzene

Many Substrates, One Major Role 305

A Lateral Player 308

“More Necessary” for Some Cells 310

To Survive at All Costs 310

A Novel Achilles’ Heel of Cancer Cells 311

The Right Weapons 312

Acknowledgments 313

12 CK2 Suppression of Apoptosis and Its Implication in Cancer Biology and Therapy 319
Janeen H. Trembley, JingJiang Wu, Gretchen M. Unger, Betsy T. Kren, and Khalil Ahmed

Introduction 319

CK2 Dynamics in Cell Growth and Cell Death 320

CK2 and Hallmarks of Cancer 323

CK2 as Target of Cancer Therapy 329

Acknowledgments 333

13 Protein Kinase CK2 in Normal and Malignant Hematopoiesis 344
Francesco Piazza

Hematopoiesis and Blood Tumors: General Concepts 344

CK2 Role in Mouse Embryonic Development: Insights into CK2 Involvement in Blood Development 345

CK2-Directed Regulation of Hematopoiesis-Associated Molecules and Signal Transduction Pathways 346

Role of CK2 in Hematologic Malignancies 351

CK2 in Blood Tumors Arising from Lymphocytes 352

CK2 in Blood Tumors Arising from Myeloid Cells 353

Conclusions 355

14 Role of CK2 in the Control of Cell Plasticity in Breast Carcinoma Progression 363
Odile Filhol, Alexandre Deshiere, and Claude Cochet

Introduction 363

Dysregulation of CK2 in Mammary Tumorigenesis 364

CK2 as a Guardian of Epithelial Cell Integrity 364

Unbalanced Expression of CK2 Subunits Is Correlated with Hypoxia and EMT-Related Markers 366

CK2β Subunit Silencing Induces EMT-Like Morphological Changes 367

Gene Expression Profiling 373

CK2β Silencing Triggers Snail1 Induction 373

Overexpression of SIX1 in CK2β-Depleted Cells 374

Conclusions 375

Acknowledgments 377

15 CK2 as a Logical Target in Cancer Therapy: Potential for Combining CK2 Inhibitors with Various Classes of Cancer Therapeutic Agents 383
Denis Drygin

Introduction 384

Suppression of Apoptosis 385

PI3K-Akt-mTOR Signaling 390

Promotion of Angiogenesis 393

Hsp90 Machinery 395

NF-κB Transcription 399

Wnt Signaling 402

Epithelial-Mesynchemal Transition 405

DNA Damage Repair 405

Other Pathways 409

Concluding Remarks 411

Acknowledgments 411

Appendix: Ck2 And Its False Sisters: The Recent Solution Of A Very “Cold Case” 440

Index 442