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. Editor 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

Table of Contents:
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