Lysophospholipid Receptors E-Book

Jerold Chun

• Herausgeber: John Wiley & Sons
• Kategorie: Wissenschaft und neue Technologien
• Sprache: Englisch

Seitenzahl: 1519

Veröffentlichungsjahr: 2013

Beschreibung

The current state of the science supporting new research in lysophospholipids

The study of lysophospholipids exploded with the discovery of cell surface receptors on both lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Since then, thousands of original research reports—ranging from fundamental cell signaling to the physiology and pathophysiology of individual organ systems—have centered on lysophospholipids. This book draws together and analyzes the current literature to provide readers with a state-of-the-science review as well as current techniques that support research in all aspects of the field of lysophospholipid signaling.

Lysophospholipid Receptors is divided into three sections:

• Receptors and other possible effectors
• Enzymes
• Physiology and pathophysiology

Within each section, the authors explain the similarities and differences between LPA and S1P signaling. Examples are provided that demonstrate the underlying mechanisms of lysophospholipid signaling across a broad range of organ systems, such as S1P signaling in cardiovascular physiology and disease and the neural effects of LPA signaling. Extensive references at the end of each chapter provide a gateway to the literature and facilitate further research into individual topics.

Each chapter has been authored by one or more leading international authorities in lysophospholipid research. Based on a thorough analysis of the current research, the authors set forth what is established science and offer their expert opinion and perspective on new and emerging areas of research, setting the stage for further investigations that will solve current problems in the field.

Leseprobe

Table of Contents

TITLE PAGE

COPYRIGHT PAGE

PREFACE

CONTRIBUTORS

CHAPTER 1 Lysophosphatidic Acid (LPA) Receptor Signaling

1.1. INTRODUCTION

1.2. LPA METABOLISM

1.3. AUTOTAXIN

1.4. LPA RECEPTORS

1.5. LPA RECEPTOR AGONISTS AND ANTAGONISTS

CHAPTER 2 Sphingosine 1-Phosphate (S1P) Receptors

2.1. INTRODUCTION

2.2. S1P METABOLISM/ENZYME, AND TRANSPORT

2.3. S1P RECEPTOR SUBTYPES, AND PHYSIOLOGICAL FUNCTIONS

2.4. CONCLUDING REMARKS

CHAPTER 3 Global Gene Expression Program of Lysophosphatidic Acid (LPA)-Stimulated Fibroblasts

3.1. INTRODUCTION

3.2. THE GLOBAL TRANSCRIPTIONAL RESPONSE OF MEFS TO LPA

3.3. UPREGULATED GENES

3.4. DOWNREGULATED GENES

3.5. INDUCTION OF GENES THAT ENCODE SECRETED FACTORS

3.6. OVERLAP BETWEEN THE EXPRESSION PROFILES OF LPA AND EGF

3.7. CONCLUSIONS

ACKNOWLEDGMENTS

CHAPTER 4 Identification of Direct Intracellular Targets of Sphingosine 1-Phosphate (S1P)

4.1. INTRODUCTION

4.2. INTRACELLULAR TARGETS FOR S1P

4.3. METHODS TO IDENTIFY INTRACELLULAR S1P TARGETS

4.4. OTHER POTENTIALLY USEFUL METHODS TO IDENTIFY LIPID BINDING PROTEINS

4.5. CONCLUDING REMARKS

ACKNOWLEDGMENTS

CHAPTER 5 Lysophospholipid Receptor Signaling Platforms: The Receptor Tyrosine Kinase–G Protein-Coupled Receptor Signaling Complex

5.1. INTRODUCTION

5.2. LYSOPHOSPHOLIPID RECEPTOR–RECEPTOR TYROSINE KINASE COMPLEXES

5.3. OTHER LYSOPHOSPHOLIPID RECEPTOR SIGNALING PLATFORMS

5.4. OTHER EXAMPLES OF RTK-GPCR SIGNALING PLATFORMS

5.5. INTERACTION OF RGS PROTEINS WITH RECEPTOR TYROSINE KINASE–LYSOPHOSPHOLIPID RECEPTOR SIGNALING COMPLEXES

5.6. S1P AND RTK TRANSACTIVATION

5.7. APPROACHES FOR THE STUDY OF RECEPTOR TYROSINE KINASE–LYSOPHOSPHOLIPID RECEPTOR SIGNALING COMPLEXES

5.8. SOME USEFUL PROTOCOLS FOR STUDYING RTK–LYSOPHOSPHOLIPID RECEPTOR SIGNALING PLATFORMS

5.9. CONCLUSION

ACKNOWLEDGMENT

CHAPTER 6 Autotaxin: A Unique Ecto-Type Pyrophosphodiesterase with Diverse Functions

6.1. HISTORY OF AUTOTAXIN (ATX)

6.2. STRUCTURE OF ATX

6.3. EXPRESSION OF ATX

6.4. ATX KNOCKOUT MICE AND TRANSGENIC MICE

6.5. ROLE OF ATX IN BLOOD VESSEL FORMATION

6.6. ROLE OF ATX IN CANCER

6.7. CLINICAL ASPECTS OF ATX

6.8. ATX INHIBITORS

6.9. AUTOTAXIN RESEARCH PERSPECTIVES

CHAPTER 7 Studies on Autotaxin Signaling in Endocytic Vesicle Biogenesis and Embryonic Development Using Whole Embryo Culture and Electroporation

7.1. INTRODUCTION

7.2. RESULTS AND DISCUSSION

7.3. METHODS

ACKNOWLEDGMENTS

CHAPTER 8 Standardization and Quantification of Lysophosphatidic Acid Compounds by Normal-Phase and Reversed-Phase Chromatography–Tandem Mass Spectrometry

8.1. PREPARATION AND HANDLING OF LYSOPHOSPHATIDIC ACID (LPA) COMPOUNDS

8.2. 1H AND 31P NMR CHARACTERIZATION

8.3. LC/MS/MS OF LPA COMPOUNDS

8.4. DISCUSSION

ACKNOWLEDGMENTS

CHAPTER 9 Sphingosine Kinases: Biochemistry, Regulation, and Roles

9.1. INTRODUCTION

9.2. SPHK STRUCTURE, ISOFORMS, AND CHARACTERISTICS

9.3. PHYSIOLOGIC AND PATHOPHYSIOLOGIC ROLES OF SPHKS

9.4. POSTTRANSLATIONAL REGULATION OF SPHK1

9.5. POSTTRANSLATIONAL REGULATION OF SPHK2

9.6. TRANSCRIPTIONAL REGULATION OF SPHKS

9.7. EXTRACELLULAR SPHKS

9.8. SPHK INHIBITORS

9.9. CONCLUSIONS

9.10. COMMON SPHK METHODS

CHAPTER 10 Functional and Physiological Roles of Sphingosine 1-Phosphate Transporters

10.1. INTRODUCTION

10.2. PHYSIOLOGICAL RELEASE OF S1P

10.3. INVOLVEMENT OF ABC TRANSPORTERS IN S1P RELEASE

10.4. THE ROLE OF THE SPNS2 TRANSPORTER IN S1P RELEASE

10.5. HUMAN SPNS2 FUNCTIONS AS AN FTY720-P TRANSPORTER

10.6. CONCLUSION

10.7. METHODS

ACKNOWLEDGMENTS

CHAPTER 11 Lipid Phosphate Phosphatases and Signaling by Lysophospholipid Receptors

11.1. INTRODUCTION AND HISTORICAL DIMENSION

11.2. CONCLUSIONS

ACKNOWLEDGMENTS

CHAPTER 12 Lipid Phosphate Phosphatases: Recent Progress and Assay Methods

12.1. INTRODUCTION

12.2. LPP NOMENCLATURE, GENE STRUCTURES, AND EXPRESSION PATTERNS

12.3. PHYSIOLOGICAL FUNCTIONS OF MAMMALIAN LPP ENZYMES REVEALED BY GENE TARGETING STUDIES IN MICE

12.4. GENETIC STUDIES OF LPPS IN NONMAMMALIAN SYSTEMS

12.5. LIPID PHOSPHATASE-RELATED PROTEINS AND PA PHOSPHATASE DOMAIN CONTAINING PROTEINS

12.6. CONCLUDING COMMENTS

12.7. DETERMINATION OF LPP ACTIVITY

ACKNOWLEDGMENTS

CHAPTER 13 Lysophosphatidic Acid (LPA) Signaling and Cardiovascular Pathology

13.1. INTRODUCTION

13.2. CIRCULATING LPA LEVELS

13.3. LPA SIGNALING IN BLOOD AND VASCULAR CELLS

13.4. REGULATION OF BLOOD PRESSURE

13.5. BLOOD VESSEL AND LYMPHATIC FORMATION

13.6. VASCULAR PERMEABILITY

13.7. VASCULAR INFLAMMATION

13.8. ATHEROTHROMBOSIS

13.9. FUTURE DIRECTIONS

ACKNOWLEDGMENTS

CHAPTER 14 Sphingosine 1-Phosphate (S1P) Signaling in Cardiovascular Physiology and Disease

14.1. SPHINGOSINE 1-PHOSPHATE (S1P) IN PLASMA: SOURCES AND CARRIERS

14.2. S1P PRODUCING AND DEGRADING ENZYMES IN THE HEART AND THE VASCULATURE

14.3. S1P RECEPTORS IN THE HEART AND VESSEL WALL

14.4. S1P SIGNALING IN CARDIAC DEVELOPMENT

14.5. S1P IN VASCULAR MORPHOGENESIS

14.6. S1P IN MYOCARDIAL REPERFUSION INJURY AND PRECONDITIONING: S1P RECEPTORS, SPHINGOSINE KINASES, AND S1P LYASE

14.7. CONTROL OF ARTERIAL TONE AND TISSUE PERFUSION BY S1P

14.8. EFFECTS ON CARDIAC FUNCTION UNDER NORMAL AND PATHOLOGICAL HEMODYNAMIC PRESSURE, AND MODULATION OF HEART RATE BY S1P

14.9. S1P IN ATHEROSCLEROSIS: MONOCYTE ADHESION AND ENDOTHELIAL PERMEABILITY

14.10. S1P IN ATHEROSCLEROSIS: LESSONS FROM S1P RECEPTOR AGONISTS AND KNOCKOUT MICE

14.11. S1P EFFECTS ON VSMCS AND THEIR IMPACT ON RESTENOSIS AFTER INJURY AND ARTERIAL REMODELING

14.12. PLASMA S1P CONCENTRATIONS INSIDE AND OUTSIDE OF HDL ARE ALTERED IN HUMAN CORONARY ARTERY DISEASE (CAD) AND MYOCARDIAL INFARCTION

14.13. FUTURE PERSPECTIVES

CHAPTER 15 Sphingosine 1-Phosphate (S1P) Signaling and the Vasculature

15.1. INTRODUCTION

15.2. S1P SYNTHESIS AND RELEASE

15.3. ANGIOGENESIS

15.4. PERMEABILITY

15.5. INFLAMMATION

15.6. VASCULAR TONE

15.7. METHODS COMMON TO THE REVIEWED FIELD

15.8. CONCLUSION

CHAPTER 16 Regulation of the Nuclear Hormone Receptor PPARγ by Endogenous Lysophosphatidic Acids (LPAs)

16.1. INTRODUCTION

16.2. METHODS PROBING PPARγ FUNCTION WITH LPA ANALOGS

16.3. SUMMARY

CHAPTER 17 Mechanisms and Models for Elucidating the Cardiac Effects of Sphingosine 1-Phosphate (S1P)

17.1. CARDIOVASCULAR EFFECTS OF SPHINGOSINE 1-PHOSPHATE (S1P) RECEPTOR SIGNALING

17.2. S1P METABOLISM, RECEPTORS, AND ACTIVATION IN THE HEART

17.3. S1P SIGNALING PATHWAYS IN THE HEART

17.4. FUNCTIONAL EFFECTS OF S1P SIGNALING IN THE HEART

17.5. CONCLUSION

ACKNOWLEDGMENT

CHAPTER 18 Neural Effects of Lysophosphatidic Acid (LPA) Signaling

18.1. INTRODUCTION

18.2. LPA SIGNALING IN NEURAL DEVELOPMENT

18.3. LPA SIGNALING IN THE ADULT NERVOUS SYSTEM

18.4. FUTURE DIRECTIONS

ACKNOWLEDGMENTS

CHAPTER 19 Widespread Expression of Sphingosine Kinases and Sphingosine 1-Phosphate (S1P) Lyase Suggests Diverse Functions in the Vertebrate Nervous System

19.1. INTRODUCTION

19.2. RESULTS AND DISCUSSION

19.3. SUMMARY

19.4. MATERIALS AND METHODS

ACKNOWLEDGMENTS

CHAPTER 20 Lysophosphatidic Acid and Neuropathic Pain: Demyelination and LPA Biosynthesis

20.1. INTRODUCTION

20.2. BASIC UNDERSTANDING OF NEUROPATHIC PAIN

20.3. LPA1 SIGNALING AND NEUROPATHIC PAIN MECHANISMS

20.4. LPA1 RECEPTOR-MEDIATED DEMYELINATION

20.5. LPA PRODUCTION

20.6. CONCLUSION

CHAPTER 21 Role of Lysophosphatidic Acid (LPA) in Behavioral Processes: Implications for Psychiatric Disorders

21.1. INTRODUCTION

21.2. BIOLOGICAL BASES OF BEHAVIOR: LPA RECEPTORS INFLUENCE NEUROCHEMISTRY AND PHYSIOLOGY AT SYNAPSES

21.3. LPA1 RECEPTOR IN LEARNING AND MEMORY

21.4. LPA1 RECEPTOR RELEVANCE FOR PSYCHIATRIC DISORDERS

ACKNOWLEDGEMENTS

CHAPTER 22 Sphingosine 1-Phosphate (S1P) Signaling and Lymphocyte Egress

22.1. REQUIREMENT FOR LYMPHOCYTE EXPRESSION OF SPHINGOSINE 1-PHOSPHATE (S1P) RECEPTORS

22.2. REQUIREMENT FOR S1P COMPARTMENTALIZATION

22.3. REGULATION OF S1PR1 EXPRESSION

22.4. METHODS TO STUDY LYMPHOCYTE EGRESS

ACKNOWLEDGMENTS

CHAPTER 23 Biology Revealed by Sphingosine 1-Phosphate (S1P) Receptor Gene-Altered Mice

23.1. INTRODUCTION

23.2. S1P1 RECEPTOR

23.3. S1P2 RECEPTOR

23.4. S1P3 RECEPTOR

23.5. S1P4 RECEPTOR

23.6. S1P5 RECEPTOR

23.7. CONCLUSION

CHAPTER 24 Role of Lysophosphatidic Acid (LPA) in the Intestine

24.1. INTRODUCTION

24.2. LPA AND LPA RECEPTORS IN THE INTESTINAL TRACT

24.3. ROLE OF LPA IN THE INTESTINAL TRACT

24.4. CONCLUDING REMARKS

24.5. METHODS

CHAPTER 25 Lysophospholipid Signaling in Female and Male Reproductive Systems

25.1. PHYSIOLOGICAL ROLES OF LYSOPHOSPHOLIPID SIGNALING IN THE FEMALE REPRODUCTIVE SYSTEM

25.2. PHYSIOLOGICAL ROLES OF LYSOPHOSPHOLIPID SIGNALING IN THE MALE REPRODUCTIVE SYSTEM

25.3. PATHOLOGICAL ROLES OF LYSOPHOSPHOLIPID SIGNALING IN THE REPRODUCTIVE SYSTEM

25.4. CLOSING REMARKS

ACKNOWLEDGMENTS

CHAPTER 26 The Gonads and Their Magic Bullet, Lysophosphatidic Acid: Physiological and Toxicological Functions of Lysophosphatidic Acid (LPA) in Female and Male Reproductive Systems

26.1. FEMALE GONADS: THE OVARIES AS TRANSIENT CELL SYSTEMS UNDER LOCAL CONTROL

26.2. QUESTIONS REGARDING THE LOCAL ROLE OF LPA

26.3. LOCAL LPA PRODUCTION IN THE OVARY

26.4. SIGNALING THROUGH LPA RECEPTORS

26.5. LPA AND ITS ROLE AS A PHENOTYPE-STABILIZING TEAMMATE WITHIN THE OVARY

26.6. LPA AS A SURVIVAL FACTOR

26.7. LPA AS REGULATOR OF STEROID PRODUCTION

26.8. POSSIBLE PATHOPHYSIOLOGICAL OR TOXICOLOGICAL RELEVANCE OF LPA IN THE OVARY

26.9. LPA AND THE MALE REPRODUCTIVE SYSTEM

26.10. LPA SIGNALING IN LEYDIG CELLS

26.11. LPA EFFECTS ON SPERMATOGENESIS

CHAPTER 27 Lysophospholipid Regulation of Lung Fibrosis

27.1. INTRODUCTION

27.2. BODY

27.3. DISCUSSION

27.4. METHODS COMMON TO THE REVIEWED FIELD

ACKNOWLEDGMENTS

CHAPTER 28 Lysophosphatidic Acid (LPA) Signaling and Bone

28.1. INTRODUCTION

28.2. LPA AND BONE CELLS

28.3. LPA RECEPTORS IN BONE CELLS

28.4. PRODUCTION OF LPA IN BONE TISSUE

28.5. LPA AND GROWTH HORMONE (GH)-BINDING PROTEIN RELEASE

28.6. BONE STATUS IN MODELS OF INVALIDATION OF LPA RECEPTORS

28.7. CONTROL OF OSSIFICATION BY GS AND GI PATHWAYS WITH REGARD TO LPA RECEPTORS

28.8. CONCLUSION

ACKNOWLEDGMENTS

CHAPTER 29 Lysophosphatidic Acid (LPA) Signaling and Bone Cancer

29.1. INTRODUCTION

29.2. LPA SIGNALING IN OSTEOLYTIC BONE METASTASES

29.3. ROLE OF LPA ON BONE RESORBING CELLS (OSTEOCLASTS)

29.4. LPA SIGNALING IN OSTEOBLASTIC BONE METASTASES

29.5. ROLE OF LPA ON BONE-FORMING CELLS (OSTEOBLASTS)

29.6. ORIGIN OF LPA AT THE BONE METASTATIC SITE

29.7. CONCLUSION

29.8. METHODS

ACKNOWLEDGMENTS

CHAPTER 30 Understanding the Functions of Lysophosphatidic Acid Receptors in Cancer

30.1. LINKING AUTOTAXIN (ATX) AND LYSOPHOSPHATIDIC ACID (LPA) RECEPTORS WITH INITIATION AND PROGRESSION OF CANCER

30.2. IMPLICATING LPA IN TUMORIGENESIS: MURINE MODELS AND HUMAN TUMORS

30.3. LPA SIGNALING AND FUNCTIONS IN CANCER BEYOND THE EDG FAMILY OF LPA RECEPTORS

30.4. TALKING TO THE NEIGHBORS: LPA RECEPTORS IN CONTEXT WITH OTHER CRITICAL PLAYERS IN CANCER

30.5. TARGETING THE LPA SIGNALING AXIS FOR CANCER THERAPY

30.6. CONCLUSIONS

ACKNOWLEDGMENTS

CHAPTER 31 Lysophosphatidic Acid Receptors in Cancer

31.1. INTRODUCTION

31.2. G PROTEIN-COUPLED RECEPTORS (GPCRS) FOR LPA

31.3. LPA1 IN CANCER

31.4. LPA2 IN CANCER

31.5. DEREGULATION OF OTHER LPA RECEPTORS IN CANCER

31.6. POTENTIAL MUTATIONS OF LPA RECEPTORS IN CANCER

31.7. ATX IN CANCER

31.8. FUTURE PROSPECTS

ACKNOWLEDGMENTS

CHAPTER 32 LPA Receptor Subtypes LPA1 and LPA2 as Potential Drug Targets

32.1. IN VITRO SCREENING ASSAYS FOR LPA1 AND LPA2 ANTAGONISTS

CHAPTER 33 Clinical Introduction of Lysophosphatidic Acid (LPA) and Autotaxin Assays

33.1. INTRODUCTION

33.2. RESULTS

33.3. DISCUSSION

33.4. METHODS

ACKNOWLEDGMENTS

CHAPTER 34 Antibodies to Bioactive Lysophospholipids

34.1. THE EMERGENCE OF BIOACTIVE LYSOPHOSPHOLIPIDS IN MODERN BIOLOGY

34.2. METHODS OF MAKING MABS TO BIOACTIVE LIPIDS: THE IMMUNEY2™ PROCESS

34.3. METHODS OF MAKING ANTI-S1P MABS

34.4. PROCEDURES FOR SCREENING FOR ANTI-S1P MABS

34.5. MEASUREMENTS OF BIOACTIVE LIPIDS AS BIOMARKERS IN BLOOD OR OTHER BIOLOGICAL FLUIDS

34.6. USE OF ANTI-S1P MABS IN BIOASSAYS AND IN VIVO EXPERIMENTS

34.7. IMMUNOLOCALIZATION OF BIOACTIVE LIPIDS IN CELL CULTURE

34.8. CLINICAL USE OF HUMANIZED ANTI-S1P MABS AS THERAPEUTIC MOLECULAR SPONGES

34.9. FUTURE DIRECTIONS

ACKNOWLEDGMENTS

INDEX

Copyright © 2013 by John Wiley & Sons, Inc. All rights reserved

Published by John Wiley & Sons, Inc., Hoboken, New Jersey

Published simultaneously in Canada

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Library of Congress Cataloging-in-Publication Data:

Lysophospholipid receptors : signaling and biochemistry / edited by Jerold Chun, Timothy Hla, Sara Spiegel, Wouter Moolenaar.

p. ; cm.

 Includes bibliographical references and index.

 ISBN 978-0-470-56905-4 (cloth)

 I. Chun, Jerold, 1959–

 [DNLM: 1. Receptors, Lysophospholipid–physiology. 2. Receptors, Lysophospholipid–metabolism. 3. Signal Transduction–physiology. QU 55.7]

 571.7'4–dc23

2012045178

PREFACE

Lysophospholipids are simple phospholipids that arise from cell membranes and related compartments. They are epitomized by two well-known species, lysophosphatidic acid (LPA) and sphingosine 1-phosphate (S1P). Studies on these lipids have shown a dramatic increase in number, from comparatively rare reports before the 1990s to what is now a vibrant and expansive scientific literature encompassing thousands of publications that range from fundamental lipid biochemistry and cell signaling to physiologies and pathophysiologies of virtually every organ system. A galvanizing event for this field’s expansion was the discovery of related cell surface G protein-coupled receptors (GPCRs) for LPA and S1P, which served to bring together scientists from many different areas. This book grew out of a desire to capture the dynamism of this field, representing both a snapshot of current knowledge as well as a single source of information for backgrounds, techniques, and literature references that encompass the current field of lysophospholipid signaling.

The book can be considered to have two parts, the first covering receptors and enzymes (Chapters 1–12), and the second covering physiology and pathophysiology (Chapters 13–34). Efforts have been made, where feasible, to pair themes common to LPA and S1P signaling, such as the receptors themselves or cardiovascular effects, in an effort to provide readers new to the field with a sampling of themes from both lipids. Complementing elements common to both lipids, such as degradative pathways mediated by lipid phosphate phosphatases, are noted, as well as distinguishing features that could provide a basis for molecular selectivity. The comprehensive index will aid access to specific topics, including methodologies.

The depth and breadth of the lysophospholipid signaling field precludes an all-encompassing treatment, and the reader is encouraged to use the provided chapters as a starting point to explore the primary literature for more thorough and timely reports. All scientific fields contain controversies and inconsistencies that are also represented within this book; rather than enforce a single viewpoint, the decision was made to provide balance with alternative views, the validity of which awaits independent study, as seen in some non-GPCR lysophospholipid mechanisms, or physiological mechanisms of lipid- targeted antisera. That said, the richness of possibilities as well as emerging data from the primary literature represent a prime example of the field’s activity and dynamism.

As important, the decision was made to leave out areas that have been superbly and extensively treated in recent reviews. A key example is the FDA approval of fingolimod—known in the scientific literature as FTY720 and commercially as Gilenya™ (Novartis AG, Basel) as the first oral treatment for relapsing forms of multiple sclerosis. Now approved worldwide, fingolimod is phosphorylated to become a non-selective S1P receptor modulator and represents the first compound targeting lysophospholipid receptors that has become a human medicine. Basic mechanisms relevant to fingolimod’s activity are, however, discussed in receptor and immunology chapters, and examples can be found in the index. Other recent areas without representation include the structural biology of lysophospholipid GPCRs, particularly the S1P receptor S1P1, as well as emerging data on newly identified lysophospholipid GPCRs for other lysophospholipid species, particularly lysophosphatidyl serine and lysophosphatidyl inositol. These topics represent areas for any future iteration of this book.

The myriad details and logistical challenges of creating this book required the efforts of many, who deserve both credit and thanks. First, this project required the efforts and vision of all of the contributors, who are integral members of the larger community of scientists whose work involves lysophospholipid signaling. Many of us were brought together through the biennial FASEB Summer Research Conferences as well as other venues such as Keystone Symposia or the ASBMB meetings; we were the organizers and sponsors of these important gatherings. Second, easily an equal number of other potential authors could have written chapters, and we thank them for both their willingness to contribute and apologize for not being able include so many worthy authors because of time and space constraints. Third, the tireless and painstaking efforts of Danielle Letourneau deserve special kudos, as she juggled every phase of this project while still handling the many demands of an active laboratory. This book would not exist without her. Fourth, we thank Anita Lekhwani, Kris Parrish, Cecilia Tsai, and all of their staff at John Wiley for their interest and infinite patience in the many—at times very slow—steps toward completing this project, particularly during Hurricane Sandy with its flooding and power outages in Hoboken and New York. Finally, we thank you, the reader, for your interest and future contributions to this growing field, and hope that this book provides you with useful and stimulating information that will lead to new scientific and medical advances through the field of lysophospholipid signaling.

Jerold ChunLa Jolla, California

CONTRIBUTORS

AIKATERINI ALEXAKI, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

MARIA L. ALLENDE, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

JUNKEN AOKI, Department of Molecular and Cellular Biochemistry, Graduate School of Pharmaceutical Sciences, Tohoku University, Miyagi, Japan

GRETCHEN BAIN, Amira Pharmaceuticals, Bristol-Myers Squibb, San Diego, CA

FABIENNE BRIAND-MÉSANGE, Molecular Signaling in Diseases of Growth, Osteogenesis and Osteolysis, Biotherapy, INSERM UMR 1043, CNRS U5282, Université Toulouse III – Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France

DAVID N. BRINDLEY, Signal Transduction Research Group, Department of Biochemistry, School of Translational Medicine, University of Alberta, Edmonton, Alberta, Canada

H. ALEX BROWN, Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN

JOAN HELLER BROWN, Department of Pharmacology, University of California, San Diego, CA

BÄRBEL BRUNSWIG-SPICKENHEIER, Clinic for Stem Cell Transplantation, Research Department Cell and Gene Therapy, Medical Faculty, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

LYGIA THERESE BUDNIK, Institute for Occupational Medicine and Maritime Medicine, Division of Occupational Toxicology and Immunology, Medical Faculty, University Medical Centre Hamburg-Eppendorf, Hamburg, Germany

ESTELA CASTILLA-ORTEGA, Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Universidad de Málaga, Málaga, Spain

JEROLD CHUN, The Scripps Research Institute, Department of Molecular Biology, Dorris Neuroscience Center, La Jolla, CA

FRANÇOISE CONTE-AURIOL, Centre d’Investigation Clinique (CIC), Module Pédiatrique, CHU de Toulouse; Molecular Signaling in Diseases of Growth, Osteogenesis and Osteolysis, Biotherapy, INSERM UMR 1043, CNRS U5282, Université Toulouse III—Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France

MARION DAVID, INSERM, Lyon, France; Université Claude Bernard Lyon 1, Lyon, France; Faculté de Médecine Lyon-Est, Lyon, France

ANPING DONG, Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY

GUILLERMO ESTIVILL-TORRÚS, Laboratorio de Investigación y Unidad de Microscopía, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, FIMABIS, Málaga, Spain

XIANJUN FANG, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

NOBUYUKI FUKUSHIMA, Department of Life Science, Kinki University, Higashiosaka, Japan

ISABELLE GENNERO, Laboratoire de Biochimie, Institut Fédératif de Biologie, CHU de Toulouse; Molecular Signaling in Diseases of Growth, Osteogenesis and Osteolysis, Biotherapy, INSERM UMR 1043, CNRS U5282, Université Toulouse III—Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France

CHRISTINA GIANNOULI, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

YONGLING GONG, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

NITAI C. HAIT, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

PEIJIAN HE, Emory University School of Medicine, Division of Digestive Diseases, Atlanta, GA

TIMOTHY HLA, Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York

KOJI IGARASHI, Bioscience Division, Reagent Development Department, AIA Research Group, TOSOH Corporation, Kanagawa, Japan

HITOSHI IKEDA, Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan; Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

KATE E. JARMAN, Centre for Cancer Biology, SA Pathology, Frome Road. Adelaide, Australia

BONGNAM JUNG, Center for Vascular Biology, Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, Cornell University, New York

JIMAN KANG, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

ATSUO KAWAHARA, Laboratory for Cardiovascular Molecular Dynamics, Riken Quantitative Biology Center, Osaka, Japan

KAZUKO KEINO-MASU, Department of Molecular Neuroscience, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

TATSUYA KISHIMOTO, Diagnostics R&D Division, Alfresa Pharma Corporation, Osaka, Japan

ELEANOR L. KOERNER, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

SEIICHI KOIKE, Department of Molecular Neuroscience, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

MARI KONO, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

SARA LAURENCIN-DALICIEUX, Molecular Signaling in Diseases of Growth, Osteogenesis and Osteolysis, Biotherapy, INSERM UMR 1043, CNRS U5282, Université Toulouse III – Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France

TAMARA M. LECLERCQ, Centre for Cancer Biology, SA Pathology, Frome Road. Adelaide, Australia

V.M. LEE, Division of Developmental Biology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI

BODO LEVKAU, Institute of Pathophysiology, University Hospital Essen, University of Duisburg-Essen, Hufelandstrasse, Essen, Germany

SHENGRONG LI, Avanti Polar Lipids, Inc., Alabaster, AL

MU-EN LIN, The Scripps Research Institute, Department of Molecular Biology, Dorris Neuroscience Center, La Jolla, CA

KEVIN R. LYNCH, Department of Pharmacology, University of Virginia, Charlottesville, VA

TIMOTHY L. MACDONALD, Department of Chemistry, University of Virginia, Charlottesville, VA

MASAYUKI MASU, Department of Molecular Neuroscience, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

AKIKO MASUDA, Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan

ALEJANDRA MENDOZA, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York

H. MENG, Division of Developmental Biology, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI

GORDON B. MILLS, Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

STEPHEN B. MILNE, Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN

SHELDON MILSTIEN, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

HOPE MIRENDIL, The Scripps Research Institute, Department of Molecular Biology, Dorris Neuroscience Center, La Jolla, CA

SHIGEKI MIYAMOTO, Department of Pharmacology, University of California, San Diego, CA

WOUTER H. MOOLENAAR, Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

JEFF D. MOORE, Avanti Polar Lipids, Inc., Alabaster, AL

KELLI MORENO, Lpath, Inc., San Diego, CA

ANDREW J. MORRIS, Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY; Department of Veterans Affairs Medical Center, Lexington, KY

ABIR MUKHERJEE, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

DIETER MÜLLER, Institute of Anatomy and Cell Biology, Signal Transduction Division, Medical Faculty, Justus-Liebig University Giessen, Giessen, Germany

DAVID S. MYERS, Department of Pharmacology, Vanderbilt University Medical Center, Nashville, TN

KAZUHIRO NAKAMURA, Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan

TSUYOSHI NISHI, Department of Cell Membrane Biology, Institute of Scientific and Industrial Research, Osaka University, Osaka, Japan; Graduate School of Pharmaceutical Sciences, Osaka University, Osaka, Japan

RYUNOSUKE OHKAWA, Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan

TAKUYA OKADA, Department of Molecular Neuroscience, Faculty of Medicine, University of Tsukuba, Tsukuba, Ibaraki, Japan

MANIKANDAN PANCHATCHARAM, Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY

NATTAPON PANUPINTHU, Department of Systems Biology, The University of Texas M. D. Anderson Cancer Center, Houston, TX

CARMEN PEDRAZA, Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Universidad de Málaga, Málaga, Spain

OLIVIER PEYRUCHAUD, INSERM, UMR-1033, Lyon, France; Université Claude Bernard Lyon 1, Lyon France; Faculté de Médecine Lyon-Est, Lyon, France

DUYEN H. PHAM, Centre for Cancer Biology, SA Pathology, Frome Road. Adelaide SA, Australia; School of Molecular and Biomedical Science, University of Adelaide, SA, Australia

MELISSA R. PITMAN, Centre for Cancer Biology, SA Pathology, Frome Road. Adelaide SA, Australia

STUART M. PITSON, Centre for Cancer Biology, SA Pathology, Frome Road. Adelaide, Australia; School of Molecular and Biomedical Science, University of Adelaide, SA, Australia

LAUREN A. PITT, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York

RICHARD L. PROIA, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

NICOLE H. PURCELL, Department of Pharmacology, University of California, San Diego, CA

NIGEL J. PYNE, Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

SUSAN PYNE, Cell Biology Group, Strathclyde Institute of Pharmacy and Biomedical Sciences, University of Strathclyde, Glasgow, UK

ANDREW D. RENAULT, Max Planck Institute for Developmental Biology, Tübingen, Germany

FERNANDO RODRÍGUEZ DE FONSECA, Laboratorio de Medicina Regenerativa, Instituto de Investigación Biomédica de Málaga (IBIMA), Hospital Regional Universitario Carlos Haya, FIMABIS, Málaga, Spain

ROGER A. SABBADINI, Lpath, Inc., San Diego, CA; Department of Biology, San Diego State University, San Diego, CA

JEAN PIERRE SALLES, Unité d’Endocrinologie, Maladies Osseuses, Gynécologie et Génétique, Hôpital des Enfants, CHU de Toulouse; Molecular Signaling in Diseases of Growth, Osteogenesis and Osteolysis, Biotherapy, INSERM UMR 1043, CNRS U5282, Université Toulouse III—Paul Sabatier, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, France

ABDEL K. SALOUS, Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY

LUIS JAVIER SANTÍN, Departamento de Psicobiología y Metodología de las Ciencias del Comportamiento, Universidad de Málaga, Málaga, Spain

SUSAN R. SCHWAB, Skirball Institute of Biomolecular Medicine, New York University School of Medicine, New York

T. JON SEIDERS, Amira Pharmaceuticals, Bristol-Myers Squibb, San Diego, CA

WALTER A. SHAW, Avanti Polar Lipids, Inc., Alabaster, AL

BARRY S. SHEA, Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA

SUSAN S. SMYTH, Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY; Department of Veterans Affairs Medical Center, Lexington, KY

SARAH SPIEGEL, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

CATELIJNE STORTELERS, Division of Cell Biology, The Netherlands Cancer Institute, Amsterdam, The Netherlands

AKIKO SUZUKI, Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

JAMES S. SWANEY, Lpath, Inc., San Diego, CA

ANDREW M. TAGER, Pulmonary and Critical Care Unit and Center for Immunology and Inflammatory Diseases, Massachusetts General Hospital, Boston, MA

CATHERINE C. THEISEN, Genetics of Development and Disease Branch, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD

GABOR TIGYI, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN

RYOKO TSUKAHARA, Department of Physiology, University of Tennessee Health Science Center, Memphis, TN

TAMOTSU TSUKAHARA, Shinshu University School of Medicine, Department of Integrative Physiology & Bio-System Control, Matsumoto, Japan

HIROSHI UEDA, Division of Molecular Pharmacology and Neuroscience, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan

GANESH VENKATRAMAN, Signal Transduction Research Group, Department of Biochemistry, School of Translational Medicine, University of Alberta, Edmonton, Alberta, Canada

BARBARA VISENTIN, Lpath, Inc., San Diego, CA

CHRISTIAN WAEBER, Stroke and Neurovascular Regulation Laboratory, Department of Radiology, Massachusetts General Hospital, Charlestown, MA

JESSICA WHEELER, Division of Cardiovascular Medicine, The Gill Heart Institute, University of Kentucky, Lexington, KY

JONATHAN M. WOJCIAK, Lpath, Inc., San Diego, CA

JINHUA WU, Department of Biochemistry and Molecular Biology, Virginia Commonwealth University School of Medicine, Richmond, VA

SUNNY YANG XIANG, Department of Pharmacology, University of California, San Diego, CA

YUTAKA YATOMI, Department of Clinical Laboratory, The University of Tokyo Hospital, Tokyo, Japan; Department of Clinical Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan

XIAOQIN YE, Department of Physiology and Pharmacology, College of Veterinary Medicine; and Interdisciplinary Toxicology Program, University of Georgia, Athens, GA

HIROSHI YUKIURA, Graduate School of Pharmaceutical Sciences, Tohoku University, Sendai, Miyagi, Japan

C. CHRIS YUN, Emory University School of Medicine, Division of Digestive Diseases, Atlanta, GA

CHAPTER 1

Lysophosphatidic Acid (LPA) Receptor Signaling

HOPE MIRENDIL, MU-EN LIN, and JEROLD CHUN

1.1. INTRODUCTION

Lysophosphatidic acid (LPA) is a simple phospholipid that has been shown to act as a potent lipid-signaling molecule. LPA acts through defined G protein-coupled receptors (GPCRs) in many developmental and adult processes involving most, if not all, vertebrate organ systems. All LPA molecules contain a phosphate head group attached to a glycerol backbone that is attached to a single aliphatic chain of varied length and saturation, typically ester-linked (with other linkages existing, e.g., alkyl-LPA) (Fig. 1.1). LPA species are present in all eukaryotic tissues at relatively low concentrations that include both structural as well as signaling pools, the latter of which can evoke myriad physiological responses in a wide variety of cell types (1–4).

Figure 1.1. LPA synthesis. LPA is mainly produced from membrane phospholipids through the two major pathways shown. Other pathways do exist for the production of LPA, as well as several degradation pathways. &18:1-LPA is the most commonly used laboratory reagent for activation of LPA receptors. &&16:0-LPA is reportedly the most abundant species in human plasma. LPE, lysophosphatidylethanolamine.

LPA was long known as a minor component of membrane phospholipid metabolism (5, 6). Hints of LPA’s possible actions as a bioactive lipid were suggested in reports dating from the early 1960s that examined smooth muscle effects including influences on blood pressure (7, 8). The chemically defined LPA species involved emerged years later with LPA’s isolation from soybeans (9). This chemical identity raised mechanistic questions on how it might function, and many theories were proposed that included physical perturbation of the membrane (10), calcium chelation (11), second messenger signaling (12), intracellular receptors (13), and cell surface receptors (14). These competing theories to explain the effects of extracellularly applied LPA as well as other lysophospholipids were clarified upon identification of the first lysophospholipid receptor: a GPCR from the brain initially named “ventricular zone gene-1” because of its expression in the embryonic neuroproliferative layer of the cerebral cortex (15) and which is now known as LPA1 (15, 16). The cloning and functional identification of this receptor gene led to the deorphanization of other putative receptor genes in the databases based upon their homology to one another (17–19). This collective group of orphan receptors was known by many different receptor names (20), the first of which was “endothelial differentiation gene” (EDG). This EDG group contained both LPA and sphingosine 1 phosphate (S1P) receptors, which underscored the significant homology among LPA and S1P receptors. At the time of the initial identification, S1P had greatest homology to LPA but was still an orphan receptor, while a homologous known receptor to LPA was the cannabinoid receptor CB1 (encoded by ) that itself interacts with endogenous lipid molecules anandamide and 2-arachidonyl glycerol (21, 22). More recently, three somewhat divergent LPA GPCRs have been identified (LPA) (23–27), which belong to the P2Y purinergic receptor family (), providing evidence for the existence of dissimilar clusters of receptors mediating the effects of the same ligand. Other species of bioactive lysophospholipids are also currently being assessed for matching receptors, though none has been identified as of yet (28). An additional dimension to LPA receptor interactions is the likelihood that different chemical forms of LPA may bind preferentially to LPA receptor subtypes (29), although the extreme difficulty of doing classical receptor binding experiments with LPA has prevented direct assessments of this possibility, relying instead on secondary readouts of receptor activity that do support ligand selectivity. All six LPA receptors are type I, rhodopsin-like GPCRs with seven transmembrane domains. Each receptor can couple to one or more of four heterotrimeric G proteins (G, G, G, and G) (), resulting in the activation of a wide range of downstream signaling pathways and resulting in diverse physiological and pathophysiological effects documented for LPA signaling.