Y. Hirabayashi, Y. Igarashi, A.H. Merrill, Jr. (Eds.)

Sphingolipid Biology

Y. Hirabayashi, Y. Igarashi, A.H. Merrill, Jr. (Eds.)

Sphingolipid Biology

With 118 Figures, Including 1 in Color

Springer

Yoshio Hi rabayash i Brain Science Insti tute, The Inst i tute of Physical and Chemical Resea rch (Riken) 2-1 Hirosawa, Wako, Sai tama 351-0198, Japan

Yasuyuki Igarashi D e p a r t m e n t of B i o m e m b r a n e and Biofunct ional Chemistry, Faculty of A d v a n c e d Life Science and G r a d u a t e School of Life Science, H o k k a i d o Univers i ty Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan

Alf red H. Merrill , Jr. School of Biology and the Peti t Inst i tute for Bioengineer ing and Bioscience, Georg ia Inst i tute of Technology At lan ta , G A 30332, U S A

ISBN-10 4-431-34198-6 Springer-Verlag Tokyo Berlin Heidelberg New York ISBN-13 978-4-431-34198-7 Springer-Verlag Tokyo Berlin Heidelberg New York

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© Springer-Verlag Tokyo 2006 Printed in Japan This work is subject to copyright. All rights are reserved, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broad- casting, reproduction on microfilms or in other ways, and storage in data banks. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regula- tions and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature.

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Foreword

We are now in the new millennium, anticipating the coming of a new age of life sciences. It should not be called the post-genomic age, denoting a mere extension of the current situation, because no one knows what it is and will be.

This book, Sphingolipid Biology, was written by leading scientists of sphingolipidomics to introduce recent discoveries in sphingolipid research. The book provides the background of those discoveries and prospects for the future, not only for specialists but also for life science in general, and sheds light on coming developments in association with other research in basic sciences as well as applied life sciences.

The progress made during the past 15 years in sphingolipid research has been remarkable. This fact is readily understood when we open a book with a title similar to the current one, namely, Sphingolipid Biochemistry, ~ edited by J.N. Kanfer and S-I Hakomori in 1983, and also a special review issue entitled "Chemistry and Metabolism of Sphingolipids," published in 1970 in the journal Chemistry and Physics of Lipids. In the latter publica- tion, one notices the work of Saul Roseman, 2 discoverer of the correct chemical structure of sialic acid, CMP-sialic acid (CMP-Neu5Ac), and the first sialyltransferase. In that issue he first proposed the concept of sphin- golipid-mediated cell-cell recognition via molecular mechanism of the ligand-receptor interactions in cell surface membranes, depicting an inter- esting fishlike model. At the time, sphingomyelin had been regarded as a

~Kanfer JN, Hakomori S-I (eds) (1983) Sphingolipid Biochemistry. Handbook of Lipid Research, vol 3. Plenum Press, New York & London

2Roseman S (1970) The synthesis of complex carbohydrates by multiglycosyl- transferase systems and their potential function in intercellular adhesion. Chem Phys Lipids 5:270-297

vi Foreword

most stubborn, mysterious molecule, metabolically and functionally, among not only sphingolipids but phospholipids themselves. No one could have anticipated the remarkable development in sphingomyelin research that has subsequently taken place. In this connection it is worth recalling the work, cited in Part 1, of Johann Ludwig Wilhelm Thudichum, discov- erer of sphingosine and cerebroside, and also the founder of neurochemis- try.

I should add the words of the late Moto-o Kimura, an eminent molecular evolutionist who proposed the concept of the neutral theory of molecular evolution. He said, "There is a great fissure between genotype (genome) and phonotype (phenome). Nobody has so far been successful in bridging the fissure." This remains our task for the future. The genome may be symbolized by the term "digital" and the phenome by "analog." It is likely that cell membrane lipids, lipid-mediated cell functions, and biosignaling are represented by analog. It is of the utmost importance to elucidate basic mechanisms of coupling between sphingolipids, phenome (analog), and genome (digital) at cellular and molecular levels. Genome (G) versus phenome (P) or phenome versus genome coupling (GVP or PVG coupling) is now proposed as a major issue in the coming post-genomic age.

As I hope is obvious from the foregoing remarks, sphingolipidomics is a subject that today increasingly involves all life scientists, for whom this volume provides a rich source of information.

Yoshitaka Nagai, Ph.D., D.Med.Sc. Professor Emeritus University of Tokyo

Contents

Foreword Yoshitaka Nagai

Contributors xiii

Part 1" Overview

1-1 Sphingolipids Synthesis, Transport and Cellular Signaling Yoshio Hirabayashi, Yasuyuki Igarashi, and Alfred H. Merrill, Jr.

Part 2: Biosynthesis, Transport of Sphingolipids

2-1 Serine Palmitoyltransferase Jia Wei, Tokumbo Yerokun, Martina Liepelt, Amin Momin, Elaine Wang, Kentaro Hanada, and Alfred H. Merrill, Jr.

2-2 Ceramide Synthase Irene Pankova-Kholmyansky and Anthony H. Futerman

2-3 Dihydroceramide: Sphinganine A4-Desaturase and C4-Hydroxylase Akemi Suzuki, Fumio Omae, and Ayako Enomoto

2-4 Metabolizing Enzymes Such As Sphingomyelin Synthase Induce Cell Death by Increasing Ceramide Content Toshiro Okazaki

25

49

57

69

viii Contents

2-5 Glucosylceramide and Galactosylceramide Synthase James A. Shayman

2-6 Synthesis, Metabolism, and Trans-Bilayer Movement of Long-Chain Base Akio Kihara and Yasuyuki Igarashi

2-7 Molecular Mechanism of Ceramide Trafficking from the Endoplasmic Reticulum to the Golgi Apparatus in Mammalian Cells Kentaro Hanada, Miyuki Kawano, and Keigo Kumagai

2-8 Sphingolipid Trafficking Kouichi Funato and Howard Riezman

2-9 Current Perspectives on Saccharomyces cerevisiae Sphingolipids Robert C. Dickson and Robert L. Lester

83

95

107

123

141

Pa r t 3: Generat ion and Degradat ion of Sphingolipid Signaling Molecules

3-1 Generation of Signaling Molecules by De Novo Sphingolipid Synthesis Kazuyuki Kitatani, L. Ashley Cowart, and Yusuf A. Hannun

3-2 Overview of Acid and Neutral Sphingomyelinases in Cell Signaling Youssef Zeidan, Norma Marchesini, and Yusuf A. Hannun

3-3 Neutral Ceramidase as an Integral Modulator for the Generation of S1P and SIP-Mediated Signaling Makoto Ito, Motohiro Tani, and Yukihiro Yoshimura

3-4 Activation of Sphingosine Kinase 1 Michael Maceyka, Sergio E. Alvarez, Sheldon Milstien, and Sarah Spiegel

3-5 Ceramide 1-Phosphate Susumu Mitsutake, Tack-Joong Kim, and Yasuyuki Igarashi

153

167

183

197

207

Contents ix

3-6 Sphingosine-l-Phosphate Lyase Julie D. Saba

219

Part 4: Membrane Domain and Biological Function

4-1 Close Interrelationship of Sphingomyelinase and Caveolin in Triton X-100-Insoluble Membrane Microdomains Keiko Tamiya-Koizumi, Takashi Murate, Katsumi Tanaka, Yuji Nishizawa, Nobuhiro Morone, Jiro Usukura, and Yoshio Hirabayashi

4-2 Roles of Membrane Domains in the Signaling Pathway for B Cell Survival Miki Yokoyama, Tomoko Kimura, Sachio Tsuchida, Hiroaki Kaku, Kiyoshi Takatsu, Yoshio Hirabayashi, and Masaki Yanagishita

4-3 The Role of Lipid Rafts in Axon Growth and Guidance Hiroyuki Kamiguchi

4-4 Sphingolipids and Multidrug Resistance of Cancer Cells Gerrit van Meer, Maarten Egmond, and David Halter

233

245

253

263

Part 5: Membrane Lipid Domain and Human Pathobiology

5-1 A New Pathological Feature of Insulin Resistance and Type 2 Diabetes: Involvement of Ganglioside GM3 and Membrane Microdomains Jin-ichi Inokuchi, Kazuya Kabayama, Takashige Sato, and Yasuyuki Igarashi

5-2 Neuronal Cell Death in Glycosphingolipidoses Yaacov Kacher and Anthony H. Futerman

5-3 Endocytic Trafficking of Glycosphingolipids in Sphingolipidoses Amit Choudhury, David L. Marks, and Richard E. Pagano

273

285

295

x C o n t e n t s

5-4 Ganglioside and Alzheimer's Disease Katsuhiko Yanagisawa

5-5 Modulation of Proteolytic Processing by Glycosphingolipids Generates Amyloid B-Peptide Irfan Y. Tamboli, Kai Prager, Esther Barth, Micheal Heneka, Konrad Sandhoff, and Jochen Walter

5-6 Hereditary Sensory Neuropathy Simon J. Myers and Garth A. Nicholson

5-7 Ceramide, Ceramide Kinase and Vision Defects: A BLIND Spot for LIPIDS Roser Gonzhlez-Duarte, Miquel Tuson, and Gemma Marfany

5-8 Fumonisin Inhibition of Ceramide Synthase: A Possible Risk Factor for Human Neural Tube Defects Ronald T. Riley, Kenneth A. Voss, Marcy Speer, Victoria L. Stevens, and Janee Gelineau-van Waes

5-9 Sphingolipids and Cancer Eva M. Schmelz and Holly Symolon

309

319

329

337

345

363

Part 6: SIP Signaling and SIPR

6-1 Sphingosine-l-Phosphate and the Regulation of Immune Cell Trafficking Maria Laura Allende and Richard L. Proia

6-2 Sphingolipids and Lung Vascular Barrier Regulation Liliana Moreno, Steven M. Dudek, and Joe G.N. Garcia

6-3 Signaling Mechanisms for Positive and Negative Regulation of Cell Motility by Sphingosine-l-Phosphate Receptors Yoh Takuwa, Naotoshi Sugimoto, Noriko Takuwa, and Yasuyuki Igarashi

6-4 Sphingosine 1-Phosphate-Related Metabolism in the Blood Vessel Yutaka Yatomi, Shinya Aoki, and Yasuyuki Igarashi

385

403

415

427

Contents xi

Part 7: Advanced Technology in Sphingolipid Biology

7-1 Conventional/Conditional Knockout Mice Ichiro Miyoshi, Tadashi Okamura, Noriyuki Kasai, Tetsuyuki Kitamoto, Shinichi Ichikawa, Soh Osuka, and Yoshio Hirabayashi

7-2 Biosynthesis and Function of Drosophila Glycosphingolipids Ayako Koganeya-Kohyama and Yoshio Hirabayashi

7-3 Characterization of Genes Conferring Resistance Against ISP-1/Myriocin-Induced Sphingolipid Depletion in Yeast Hiromu Takematsu and Yasunori Kozutsumi

7-4 Lysenin" A New Probe for Sphingomyelin Toshihide Kobayashi and Akiko Yamaji-Hasegawa

7-5 Structural Biology of Sphingolipid Synthesis Hiroko Ikushiro, Akihiro Okamoto, and Hideyuki Hayashi

7-6 A Computer Visualization Model for the De Novo Sphingolipid Biosynthetic Pathway Jin Young Hong, Jeremy C. Allegood, Samuel Kelly, Elaine Wang, Alfred H. Merrill Jr., and May Dongmei Wang

443

453

463

475

483

493

Appendix

I. lnhibitors of Sphingolipid Biosynthesis Jin-ichi Inokuchi

II. The Genes in Yeast and Mammals Yasuyuki Igarashi, Akio Kihara, and Yoshio Hirabayashi

III. Structure of Glycosphingolipids and Metabolic Pathway Akemi Suzuki

511

515

519

Keyword Index 529

Contributors

Jeremy C. Allegood School of Biology and the Petit Institute of Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Maria Laura Allende Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA

Sergio E. Alvarez Department of Biochemistry, Virginia Commonwealth University Medical Center and the Massey Cancer Center, Richmond, Virginia 23298, USA

Shinya Aoki Department of Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan

Esther Barth Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany

Amit Choudhury Department of Biochemistry and Molecular Biology, Thoracic Dis- eases Research Unit, Mayo Clinic and Foundation, Rochester, Min- nesota 55905, USA

L. Ashley Cowart Department of Biochemistry and Molecular Biology, Medical Uni- versity of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29402, USA

xiv Contributors

Robert C. Dickson Department of Cellular and Molecular Biochemistry and the Lucille P. Markey Cancer Center, University of Kentucky College of Medi- cine, Lexington, KY 40536-0298, USA

Steven M. Dudek Department of Medicine, University of Chicago, 5841 South Mary- land Avenue, Chicago, Illinois 60637, USA

Maarten Egmond Department of Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands

Ayako Enomoto Sphingolipid Expression Laboratory, RIKEN Frontier Research Sys- tem, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Kouichi Funato Graduate School of Biosphere Science, Faculty of Applied Biological Science, Hiroshima University, 1 -4-4 Kagamiyama, Higa- shi-Hiroshima 739-8528, Japan

Anthony H. Futerman Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

Joe G.N. Garcia Department of Medicine, University of Chicago, 5841 South Mary- land Avenue, Chicago, Illinois 60637, USA

Janee Gelineau-van Waes Department of Genetics, Cell Biology & Anatomy, University of Ne- braska Medical Center, Omaha, Nebraska 68198-5455, USA

Roser Gonz~lez-Duarte Departament de Gen~tica, Facultat de B iologia, Universitat de Barce- lona, Spain

Contributors xv

David Halter Department of Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands

Kentaro Hanada Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan

Yusuf A. Hannun Department of Biochemistry and Molecular Biology, Medical Uni- versity of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29425, USA

Hideyuki Hayashi Department of Biochemistry, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan

Micheal Heneka Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany

Yoshio Hirabayashi Brain Science Institute, The Institute of Physical and Chemical Re- search (RIKEN), 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Jin Young Hong The Wallace H. Coulter Department of Biomedical Engineering and the Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA

Shinichi lchikawa Department of Applied Life Sciences, Niigata University of Phar- macy and Applied Life Sciences, Niigata 956-8603, Japan

Yasuyuki lgarashi Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan

xvi Contributors

Hiroko Ikushiro Department of Biochemistry, Osaka Medical College, Takatsuki, Osaka 569-8686, Japan

Jin-ichi Inokuchi Department of Biomembrane and Biofunctional Chemistry and CREST, Japan Science and Technology Agency, Graduate School of Pharmaceutical Sciences, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21, Nishi 11, Kita-ku, Sapporo 001-0021, Japan

Makoto lto Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Hakozaki 6-10-1, Fukuoka 812-8581, Japan Bio-archtechture Center, Kyushu University, Hakozaki 6-10-1, Fu- kuoka 812-8581, Japan

Kazuya Kabayama CREST, Japan Science and Technology Agency, Graduate School of Pharmaceutical Sciences, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21, Nishi 11, Kita-ku, Sapporo 001-0021, Japan

Yaacov Kacher Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

Hiroaki Kaku Division of Immunology, Department of Microbiology and Immu- nology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirogane-dai, Minato-ku, Tokyo 108-8639, Japan

Hiroyuki Kamiguchi Laboratory for Neuronal Growth Mechanisms, RIKEN Brain Science Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Noriyuki Kasai Institute for Animal Experimentation, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan

Contributors xvii

Miyuki Kawano Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan

Samuel Kelly School of Biology and the Petit Institute of Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Akio Kihara Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan

Tack-Joong Kim Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan

Tomoko Kimura Department of Hard Tissue Engineering, Biochemistry, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan

Tetsuyuki Kitamoto Department of Neurological Science, Tohoku University Graduate School of Medicine, Sendai 980-8575, Japan

Kazuyuki Kitatani Department of Biochemistry and Molecular Biology, Medical Uni- versity of South Carolina, 173 Ashley Avenue, Charleston, South Carolina 29402, USA

Toshihide Kobayashi Lipid Biology Laboratory, RIKEN (Institute of Physical and Chemi- cal Research) Discovery Research Institute, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan Supra-Biomolecular System Research Group, RIKEN Frontier Re- search System, Saitama 351-0198, Japan INSERM U585, INSA (Institut National des Sciences Appli- quees)-Lyon, 20 Ave A. Einstein, 69621 Villeurbanne, France

xviii Contributors

Ayako Koganeya-Kohyama Hirabayashi Laboratory Unit, Brain Science Institute, RIKEN, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Yasunori Kozutsumi Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan CREST, JST, Kawaguchi, Saitama, Japan Supra-biomolecular System Research Group, Frontier Research Sys- tem, RIKEN, Saitama 351-0198, Japan

Keigo Kumagai Department of Biochemistry and Cell Biology, National Institute of Infectious Diseases, 1-23-1 Toyama, Shinjuku-ku, Tokyo 162-8640, Japan

Robert L. Lester Department of Cellular and Molecular Biochemistry and the Lucille P. Markey Cancer Center, University of Kentucky College of Medi- cine, Lexington, KY 40536-0298, USA

Martina Liepelt School of Biology and the Petit Institute for Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Michael Maceyka Department of Biochemistry, Virginia Commonwealth University Medical Center and the Massey Cancer Center, Richmond, Virginia 23298, USA

Norrna Marchesini Department of Biochemistry and Molecular Biology, Medical Uni- versity of South Carolina, Charleston, SC 29425, USA

Gemma Marfany Departament de Gen6tica, Facultat de Biologia, Universitat de Barce- lona, Spain

Contributors xix

David L. Marks Department of Biochemistry and Molecular Biology, Thoracic Dis- eases Research Unit, Mayo Clinic and Foundation, Rochester, Min- nesota 55905, USA

Alfred H. Merrill Jr. School of Biology and the Petit Institute of Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Sheldon Milstien Laboratory of Cellular and Molecular Regulation, National Institute of Mental Health, Bethesda, MD 20892, USA

Susumu Mitsutake Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan

lchiro Miyoshi Center for Experimental Animal Science, Nagoya City University Graduate School of Medical Sciences, Nagoya 467-8601, Japan

Amin Momin School of Biology and the Petit Institute for Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Liliana Moreno Department of Medicine, University of Chicago, 5841 South Mary- land Avenue, Chicago, Illinois 60637, USA

Nobuhiro Morone Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

Takashi Murate Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan

Simon J. Myers Northcott Neuroscience Laboratory, ANZAC Research Institute, Hos- pital Rd, Concord, Sydney, NSW 2139, Australia

XX Contributors

Garth A. Nicholson Northcott Neuroscience Laboratory, ANZAC Research Institute, Hos- pital Rd, Concord, Sydney, NSW 2139, Australia Department of Molecular Medicine, Concord Repatriation General Hospital, Hospital Rd, Concord, Sydney, NSW 2139, Australia

Yuji Nishizawa Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

Akihiro Okamoto Department of Biological Science & Technology, School of High-Technology for Human Welfare, Tokai University, Numazu, Shizuoka 410-0395, Japan

Tadashi Okamura Department of Infectious Diseases, Research Institute, International Medical Center of Japan, Tokyo 162-8655, Japan

Toshiro Okazaki Department of Clinical Laboratory Medicine/Hematology, Faculty of Medicine, Tottori University, Yonago, Tottori 683-8504, Japan

Fumio Omae Sphingolipid Expression Laboratory, RIKEN Frontier Research Sys- tem, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Soh Osuka CREST and Neuronal Circuit Mechanism Research Group, RIKEN Brain Science Institute, Saitama, Japan

Richard E. Pagano Department of Biochemistry and Molecular Biology, Thoracic Dis- eases Research Unit, Mayo Clinic and Foundation, Rochester, Min- nesota 55905, USA

Irene Pankova-Kholmyansky Department of Biological Chemistry, Weizmann Institute of Science, Rehovot 76100, Israel

Contributors xxi

Kai Prager Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany

Richard L. Proia Genetics of Development and Disease Branch, National Institutes of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD 20892, USA

Howard Riezman Department of Biochemistry, University of Geneva, Sciences II, 30, quai E. Ansermet, CH-1211 Geneva 4, Switzerland

Ronald T. Riley Toxicology and Mycotoxin Research Unit, United States Department of Agriculture-Agricultural Research Service, PO Box 5677, Athens, Georgia 30604, USA

Julie D. Saba Children's Hospital Oakland Research Institute, 5700 Martin Luther King Jr. Way, Oakland, CA 94609, USA

Konrad Sandhoff Kekul6-Institute for Organic Chemistry and Biochemistry, University of Bonn, Gerhard-Domagk-Strasse 1, 53121 Bonn, Germany

Takashige Sato Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Frontier Research Center for Post-Genomic Science and Technology, Hokkaido University, Kita 21-Nishi 11, Kita-ku, Sapporo 001-0021, Japan

Eva M. Schmelz Karmanos Cancer Institute, Wayne State University School of Medi- cine, HWCRC 608, 110 E. Warren Avenue, Detroit, MI 48201, USA. School of Biology and the Petit Institute for Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

xxii Contributors

James A. Shayman Department of Internal Medicine, Division of Nephrology, University of Michigan, 1560 MSRB II, 1150 West Medical Center Drive, Ann Arbor, Michigan 48109-0676, USA

Marcy Speer Duke Center for Human Genetics, School of Medicine, Duke Univer- sity, Durham, North Carolina 27710, USA

Sarah Spiegel Department of Biochemistry, Virginia Commonwealth University Medical Center and the Massey Cancer Center, Richmond, Virginia 23298, USA

Victoria L. Stevens Epidemiology and Surveillance Research, American Cancer Society, Atlanta, Georgia, USA

Naotoshi Sugimoto Department of Physiology, Kanazawa University Graduate School of Medicine, 2-6-11 Takara-machi, Kanazawa 920-8640, Japan

Akemi Suzuki Sphingolipid Expression Laboratory, RIKEN Frontier Research Sys- tem, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan

Holly Symolon Karmanos Cancer Institute, Wayne State University School of Medi- cine, HWCRC 608, 110 E. Warren Avenue, Detroit, MI 48201, USA School of Biology and the Petit Institute for Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Kiyoshi Takatsu Division of Immunology, Department of Microbiology and Immu- nology, Institute of Medical Science, University of Tokyo, 4-6-1 Shirogane-dai, Minato-ku, Tokyo 108-8639, Japan

Hiromu Takematsu Laboratory of Membrane Biochemistry and Biophysics, Graduate School of Biostudies, Kyoto University, Kyoto 606-8501, Japan CREST, JST, Kawaguchi, Saitama, Japan

Contributors xxiii

Noriko Takuwa Department of Physiology, Kanazawa University Graduate School of Medicine, 2-6-11 Takara-machi, Kanazawa 920-8640, Japan

Yoh Takuwa Department of Physiology, Kanazawa University Graduate School of Medicine, 2-6-11 Takara-machi, Kanazawa 920-8640, Japan

Irfan Y. Tamboli Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany

Keiko Tamiya-Koizumi Nagoya University Graduate School of Medicine, Nagoya 461-8673, Japan

Katsumi Tanaka Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

Motohiro Tani Department of Biomembrane and Biofunctional Chemistry, Graduate School of Pharmaceutical Sciences, Hokkaido University, Kita 12, Nishi 6, Kita-ku, Sapporo 060-0812, Japan

Saehio Tsuehida Department of Hard Tissue Engineering, Biochemistry, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan

Miquel Tuson Departament de Genbtica, Facultat de B iologia, Universitat de Barce- lona, Spain

Jiro Usukura Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan

xxiv Contributors

Gerrit van Meer Department of Membrane Enzymology, Bijvoet Center and Institute of Biomembranes, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands

Kenneth A. Voss Toxicology and Mycotoxin Research Unit, United States Department of Agriculture-Agricultural Research Service, PO Box 5677, Athens, Georgia 30604, USA

Jochen Walter Department of Neurology, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany

Elaine Wang School of Biology and the Petit Institute of Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

May Dongmei Wang The Wallace H. Coulter Department of Biomedical Engineering, and the Petit Institute of Bioengineering and Bioscience, Georgia Institute of Technology, Atlanta, GA 30332, USA

Jia Wei School of Biology and the Petit Institute for Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Akiko Yamaji-Hasegawa Laboratory of Cellular Biochemistry, RIKEN Discovery Research In- stitute, Saitama 351-0198, Japan

Katsuhiko Yanagisawa Department of Alzheimer's Disease Research, National Institute for Longevity Sciences, National Center for Geriatrics and Gerontology, 36-3 Gengo, Morioka, Obu 474-8522, Japan

Masaki Yanagishita Department of Hard Tissue Engineering, Biochemistry, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan

Contributors xxv

Yutaka Yatomi Department of Laboratory Medicine, Graduate School of Medicine, The University of Tokyo, Tokyo 113-8655, Japan

Tokumbo Yerokun School of Biology and the Petit Institute for Bioengineering and Bio- science, Georgia Institute of Technology, Atlanta, GA 30332, USA

Miki Yokoyama Department of Hard Tissue Engineering, Biochemistry, Division of Bio-Matrix, Graduate School, Tokyo Medical and Dental University, 1-5-45 Yushima, Bunkyo-ku, Tokyo 113-8549, Japan

Yukihiro Yoshimura Department of Bioscience and Biotechnology, Graduate School of Bioresource and Bioenvironmental Sciences, Kyushu University, Hakozaki 6-10-1, Fukuoka 812-8581, Japan

Youssef Zeidan Department of Biochemistry and Molecular Biology, Medical Uni- versity of South Carolina, Charleston, SC 29425, USA

Acknowledgment

We are deeply indebted to Bonnie Lee La Madeleine, Brain Science Institute, RIKEN,

for her excellent editorial assistance.