~ Pergamon Prog. Lipid Res. Vol. 36, No. 2/3, pp. 153-195, 1997 © 1997 Published by ElsevierScience Ltd. All rights reserved Printed in Great Britain PII: S0163-7827(97)00008-8 0163-7827/97/$32.00 THE ROLE OF SPHINGOLIPIDS IN THE PROCESS OF SIGNAL TRANSDUCTION Laura Riboni, Paola Viani, Rosaria Bassi, Alessandro Prinetti and Guido Tettamanti* Department of Medical Chemistry and Biochemistry, Medical Faculty, University of Milan, Via Saldini 50, 20133 Milan, Italy CONTENTS I. Introduction 154 II. Chemical, physicochemical and aggregation properties of sphingolipids 154 A. Basic chemical properties 154 B. Confotmational and physicochemical properties 155 C. Aggregation properties ! 58 III. Metabolic pathways of sphingolipids: subcellular location and topology of the inwglved enzymes 159 A. Sphingoid bases and ceramide 159 B. Sphingomyelin 163 C. Glucosyl ceramide, galactosyl ceramide and sulphatide 164 D. Gangliosides and allied neutral oligoglycosyl sphingolipids 166 1. De novo biosynthesis 166 2. Degradation 167 3. Direct glycosylation 168 4. Salvage pathways 168 5. Ganglioside turnover 169 6. Ganglioside metabolism in the plasma membrane 170 IV. Cellular and subcellular location of sphingolipids 170 V. Binding and receptor properties of sphingolipids 171 VI. Sphingolipids in signal transduction 171 A. Activation of sphingolipid signalling 174 B. KirLetics of sphingolipid signalling 175 C. Enzymes involved in sphingolipid signalling 175 VII. Intrao,~llular targets of sphingoid molecule-mediated signalling 179 A. Direct specific targets of sphingoid biomediators 180 B. Effects of sphingoid biomediators on constituents of other signalling pathways 181 1. Enzymes involved in the production of glycerophospholipid signalling 181 (a) Phospholipase D and phosphatidic acid metabolism 182 (b) Phospholipase C 182 (c) Phospholipase A2 183 2. Cyclic AMP (cAMP) 183 3. Receptor-associated tyrosine kinases and other tyrosine kinases 183 4. Serine/threonine kinases 184 (a) Protein kinase C 184 (b) Mitogen-activated protein kinases and stress-activated protein kinases 184 5. Other kinases 184 6. Calcium signalling 185 VIII. Sphingolipids and gene expression modulation 185 IX. Conclusion and perspectives 186 Refer,.~nces 186 ABBREVIATIONS Ganglioside nomenclature is according to Svennerholm4s4 AP-I Ara-C bFGF cAMP CAPK Cox cPLA2 activ~,tor protein 1 DAG cytosine 13-o-arabinofuranoside DAGK basic fibroblast growth factor EGF adenosine 3',5'-cyclic monophosphate EGFRK cerarnide-activated protein kinase HIV cyclooxygenase ICE cytosolic phospholipase A: IGF diacylglycerol diacylglycerol kinase epidermal growth factor epidermal growth factor receptor kinase human immunodeficiency virus interleukin converting enzyme insulin-like growth factor *Correspondence to: Professor Guido Tettamanti, Department of Medical Chemistry and Biochemistry, Via Saldini 50, 20133 Milan, Italy. Tel.: +39-2-70645247; Fax: +39-2-2363584; E-mail: tettaman@ imiucca.csi.unimi.it. 153