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1、focuSonLIPIDSREVIEWSPrinciplesofbioactivelipidsignalling:lessonsfromsphingolipidsYusufA.Hannun*andLinaM.Obeid‡§Abstract
2、Ithasbecomeincreasinglydifficulttofindanareaofcellbiologyinwhichlipidsdonothaveimportant,ifnotkey,rolesassignallingandregulatorymolecules.Therapidlyexpand
3、ingfieldofbioactivelipidsisexemplifiedbymanysphingolipids,suchasceramide,sphingosine,sphingosine-1-phosphate(S1P),ceramide-1-phosphateandlyso-sphingomyelin,whichhaverolesintheregulationofcellgrowth,death,senescence,adhesion,migration,inflammation,angiogenesisandintracellula
4、rtrafficking.Decipheringthemechanismsofthesevariedcellfunctionsnecessitatesanunderstandingofthecomplexpathwaysofsphingolipidmetabolismandthemechanismsthatregulatelipidgenerationandlipidaction.DAGAlthoughtheconceptof‘bioactivelipids’—broadlyphospholipidmetabolism,suchasphosp
5、hatidylinositol-sn‑1,2‑diacylglycerolisakeydefinedaschangesinlipidlevelsthatresultinfunctional3,4,5-trisphosphate(PtdIns(3,4,5)P),alsoserveaskey3metabolicintermediateinconsequences—hasbeendecadesinthemaking,ithasintermediatesincellsignalling.Otherglycerolipid-glycerolipidsy
6、nthesisthatalsoonlystartedtogaintractioninthepast20years,andderivedregulatorymoleculesincludephosphatidicacidservesasasecondmessengerpromisestooccupycentre-stageincellbiologyresearch(PA),monoacylglycerolsandanandamide(candidateinregulatingclassicalandnovelproteinkinaseCenzy
7、mes.inthetwenty-firstcentury.Thisbelatedrecognitionhasligandsforcannabinoidreceptors),lyso-phosphatidicitsrootsinearlierpreconceivedideasaboutexclusiveacidandplateletactivatingfactor(PAF).ProteinkinaseCrolesforlipidsinenergymetabolismandinmembraneAnothergroupofbioactivelipi
8、dsthathavecometo(PKC).Afamilyofcloselystructure,whichhavepreventedwiderthinkingabouttheforegroundinthepasttwodecadesarethesphingo-relatedproteinkinasesthatarefunctionallipidsbynon-lipidologists.Theseimped-lipids.Thefirstofthesetobeidentifiedwassphingosine,highlyconservedint
9、heircatalyticdomains.Classicalimentsprimarilyarisefromthemanyinherentdiffi-whichex