Class II Phosphoinositide 3-Kinases Contribute to Endothelial Cells Morphogenesis.docVIP

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Class II Phosphoinositide 3-Kinases Contribute to Endothelial Cells Morphogenesis.doc

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Class II Phosphoinositide 3-Kinases Contribute to Endothelial Cells Morphogenesis

ClassIIPhosphoinositide3-KinasesContributeto EndothelialCellsMorphogenesis GianpaoloTibolla1,2,3.,RobertoPin?eiro1.,DanielaChiozzotto1,IoannaMavrommati1,AnnP.Wheeler4, GiuseppeDaniloNorata1,2,3,AlbericoLuigiCatapano2,5,TaniaMaffucci1,MarcoFalasca1* 1QueenMaryUniversityofLondon,BartsandTheLondonSchoolofMedicineandDentistry,BlizardInstitute,CentreforDiabetes,InositideSignallingGroup,London, UnitedKingdom,2DepartmentofPharmacologicalandBiomolecularSciences,UniversityofMilan,Milan,Italy,3CenterfortheStudyofAtherosclerosis,Societa` Italiana Studio Aterosclerosi, Bassini Hospital, Cinisello Balsamo, Italy, 4Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard AdvancedLightMicroscopyCoreFacility,London,UnitedKingdom,5IstitutodiRicercaeCuraaCarattereScientificoMultiMedica,Milan,Italy Abstract Thequestionofwhetherthedistinctisoformsofthefamilyofenzymesphosphoinositide3-kinases(PI3Ks)playredundant roleswithinacellorwhethertheycontroldistinctcellularprocessesordistinctstepswithinthesamecellularprocesshas gained considerable importance in the recent years due to the development of inhibitors able to selectively target individualisoforms. ItisimportanttounderstandwhetherinhibitionofonePI3Kcanresultincompensatoryeffect from otherisoform(s)andthereforewhetherstrategiesaimedatsimultaneouslyblockingmorethanonePI3Kmaybeneeded.In thisstudyweinvestigatedtherelativecontributionofdistinctPI3Kisoformstoendothelialcells(EC)functionsspecifically regulatedbythesphingolipidsphingosine-1-phosphate(S1P)andbyhighdensitylipoproteins(HDL),themajorcarrierof S1Pinhumanplasma.Hereweshowthataco-ordinatedactionofdifferentPI3Ksisrequiredtotightlyregulateremodelling ofEConMatrigel,aprocessdependentoncellproliferation,apoptosisandmigration.Thecontributionofeachisoformto thisprocessappearstobedistinct,withtheclassIIenzymePI3K-C2bandtheclassIBisoformp110cmainlyregulatingthe S1P-andHDL-dependentECmigrationandPI3K-C2aprimarilycontrollingECsurvival.Da