Post‑Transcriptional Regulation by STAR Proteins (eBook)

Talila Volk is an associate professor in the field of Developmental Biology and the incumbent of the Sir Ernest B. Chain Professional Chair. Her major research interest is in tissue morphogenesis and organogenesis during embryonic development. She has been studying the function and activity of the STAR family member Held Out Wing (HOW) in the fruit fly Drosophila since 1999. She served as the chair for the Society of Developmental Biology in Israel (ISDB). Dr. Volk has gained her BSc from Tel‑Aviv University, and her MSc and PhD degrees from the Weizmann Institute of Science, Rehovot, Israel. Karen Artzt is an Ashbel Smith Professor Emeritus at the University of Texas at Austin where she directed a research laboratory for 20 years. There she was a member of the Section of Molecular Genetics and Microbiology. Prior to that she was an associate Member of the Memorial Sloan Kettering Cancer Center in New York. Her main research interests include developmental genetics with an emphasis on cancer biology. In collaboration with Tom Ebersole she identified and cloned the mouse gene quaking that was one of the founding members of the STAR family. Dr. Artzt received her academic degrees from Cornell university; a BA from the Ithaca campus and a PhD from the Medical College School of Graduate Sciences in New York City. In 1972 she spent a year as a postdoctoral fellow at the Pasteur Institute in Paris under the direction of the Nobel Prize winner, Francois Jacob.

Title Page 3
Copyright Page 4
DEDICATIONS 5
PREFACE 6
ABOUT THE EDITORS... 7
ABOUT THE EDITORS... 8
PARTICIPANTS 9
Table of Contents 11
CHAPTER 1. STAR TREK AN INTRODUCTION TO STAR FAMILY PROTEINS AND REVIEW OF QUAKING (QKI) 15
History of the STAR Family 15
The Domain Structure and Alternate Splicing of STAR Proteins 18
STAR Proteins Have a Multitude of Developmental Functions 19
Diverse Molecular Functions of STAR Proteins in RNA Processing 19
Qk Expression in the Adult Nervous System and Disease 20
Qk 3' UTR Conservation and a High Theoretical Number of miRNA Binding Sites 22
Discussion and Conclusion 25
Future Applications, New Research, Anticipated Developments 35
REFERENCES 35
CHAPTER 2. THE STAR FAMILY MEMBER QKI AND CELL SIGNALING 39
Introduction 39
QKI Is Essential for Embryonic and Postnatal Development 40
Phosphorylation of QKI Isoforms by Src-PTKS Regulates the Cellular Fate of QKI mRNA Targets at Multiple Post-Transcriptional Steps 41
Numerous Extracellular Signals Can Be Linked to the Src-PTK-QKI Pathway 44
Potential Role of QKI And Src-PTK Signaling in Tumorigenesis and Cognitive Diseases 46
Conclusion 47
REFERENCES 48
CHAPTER 3. INSIGHTS INTO THE STRUCTURAL BASIS OF RNA RECOGNITION BY STAR DOMAIN PROTEINS 51
Introduction 51
The STAR Domain 53
RNA Recognition by STAR Proteins 53
Recognition of RNA by GLD-1 54
Recognition of RNA by QKI 54
RNA Recognition by Other STAR Domain Proteins 56
Star Domain Structure 57
The NMR Structure of SF1 Bound to RNA 57
Overview of the Structure 57
Recognition of RNA by SF1 59
The NMR Structure of the KH and QUA2 Regions of QKI 61
Conservation of RNA Contact Residues between SF1 and STAR Proteins 62
Conclusion 64
Note Added in Proof 64
REFERENCES 65
CHAPTER 4. POST-TRANSLATIONAL REGULATION OF STAR PROTEINS AND EFFECTS ON THEIR BIOLOGICAL FUNCTIONS 68
Introduction 69
Sam68: A Brief Overview 69
Regulation of Sam68 Functions by Tyrosine Phosphorylation 71
Regulation of Sam68 Functions by Serine/Threonine Phosphorylation 73
Regulation of Sam68 Functions by Methylation 74
Regulation of Sam68 Functions by Acetylation and Sumoylation 75
POST-TRANSLATIONAL MODIFICATIONS OF SLM-1 AND SLM-2 75
POST-TRANSLATIONAL MODIFICATIONS OF THE QKI PROTEINS 76
POST-TRANSLATIONAL MODIFICATIONS OF SF1 77
Conclusion 77
REFERENCES 78
CHAPTER 5. EXPRESSION AND FUNCTIONS OF THE STAR PROTEINS Sam68 AND T-STAR 
81 
Gene Expression Control in Spermatogenesis 81
Expression of STAR Proteins during Spermatogenesis 84
PROTEIN STRUCTURE AND MODIFICATIONS 84
MOUSE KNOCKOUT MODELS DEFINE THE ROLES OF STAR PROTEINS 
90 
The STAR Protein Sam68 Is Involved in Translational Control in Spermatogenesis 90
STAR Proteins Might Play Roles in Pre-mRNA Splicing Control in Spermatogenesis 91
Other Potential Roles of STAR Proteins in Spermatogenesis 92
Conclusion 92
REFERENCES 93
CHAPTER 6. THE ROLE OF QUAKING IN MAMMALIAN EMBRYONIC DEVELOPMENT 96
Introduction 97
Quaking Is Required for the Formation of Embryonic Vasculature 98
QKI5 Regulates QKI6 and QKI7 in Visceral Endoderm 98
Molecular Basis of Blood Vessel Formation 99
Quaking Is Required for Visceral Endoderm Differentiated Function 100
Other Possible Roles for Quaking in Cardiovascular Development 102
The Evolving Roles of Quaking Function 102
Conclusion 103
REFERENCES 104
CHAPTER 7. DROSOPHILA STAR PROTEINS: WHAT CAN BE LEARNED FROM FLIES? 107
STAR Proteins in Drosophila 107
HOW Regulates Differentiation of Diverse Tissues 108
Structural Hallmarks and Binding Specificty of HOW 108
Functional Analysis of HOW in the Drosophila Embryo 108
HOW and Kep1 Regulate Cell Division and Apoptosis in Drosophila 114
HOW Mediates Cell Cycle Arrest in the Mesoderm of Gastrulating Embryos 114
Kep1 and HOW Promote the Apoptotic Process in Drosophila 116
Conclusion 117
Note Added in Proof 118
REFERENCES 118
CHAPTER 8. C. ELEGANS STAR PROTEINS, GLD-1 AND ASD-2, REGULATE SPECIFIC RNA TARGETS TO CONTROL DEVELOPMENT 120
Multiple Functions of GLD-1 in Germline Development 120
GLD-1 Molecular Analysis 123
mRNA Targets: GLD-1 Is a Translational Repressor 124
mRNA Targets: Further Insights into GLD-1 Function in Germline Development 128
mRNA TARGETS: TOWARDS DEFINING THE GLD-1 RNA BINDING 
129 
How Is GLD-1 Expression Regulated? 131
ASD-2, Another C. elegans STAR Protein, Functions in Alternative Splicing 133
Conclusion 133
CHAPTER 9. THE BRANCHPOINT BINDING PROTEIN: IN AND OUT OF THE SPLICEOSOME CYCLE 137
BBP AND SF1 ARE SITE-SPECIFIC RNA BINDING PROTEINS 138
A BBP-Mud2 Heterodimer Functions in Branchpoint Recognition 140
BBP-MUD2 and the Dynamics of Early Spliceosome Assembly 141
Co-Transcriptional Pre-mRNA Splicing 144
But Is BBP Really an Essential Splicing Factor? 145
BBP Is Needed for the Nuclear Retention of Unprocessed Pre-mRNA 145
Uncoupling Pre-mRNA Splicing from the Synthesis of Functional mRNA 147
Does BBP Have a Cytoplasmic Function? 147
Does BBP Regulate the Fate of Intronless RNA? 148
Conclusion 149
REFERENCES 150
CHAPTER 10. Reaching for the STARS Linking RNA Binding Proteins to Diseases 156
Sam68: Its Discovery and Nomenclature 156
The KH Domain 157
Sam68 RNA Targets 159
Sam68 Cellular Localization 160
Sam68 Signaling Motifs 161
Arginine Methylation 162
STAR Protein Mouse Models 163
Sam68 Null Mice 163
QKI Mouse Models 164
STAR Proteins and Human Diseases 165
Osteoporosis 165
Schizophrenia 166
Ataxia 166
Cancer 166
Conclusion 167
REFERENCES 167
INDEX 172