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1、ThePI3K/Akt/mTORpathwayplaysanimportantroleinapoptosis.ActivatedPI3Kgeneratesphosphatidylinositol-3,4,5-triphosphate,whichrecruitsPDK1andAktserine/threoninekinaseattheplasmamembrane.ThisresultsinactivationofAkt.?Aktactivatesmultipledownstreamtargets,includingthemTOR
2、pathway.Aktinthispatywayisflankedbytwotumorsuppressors,PTENandTSC1/TSC2heterodimer.Variousreceptortyrosinekinases(RTKs),suchashumanepidermalgrowthfactorreceptor2(HER2),epidermalgrowthfactorreceptor(EGFR),insulin-likegrowthfactorreceptorandvascularendothelialgrowthfa
3、ctorreceptor,activatethegrowthandsurviveofcellsinthemannerofmobilizingtheintracellularPI3Ksignalingpathway[12;36].ThecarcinogenicroleofthePI3Kpathwayfirstlycameintothenoticesincemutation-inducedabnormalcellularsignalingwasassociatedwithmalignantproliferationandgrowt
4、h[58].IncreasingevidenceindicatedthatPI3Ksignalingpathwaywasusuallyfoundtobedisorderedinmanykindsofcancers.THEPI3KFAMILYMEMBERSAllPI3Kfamilymembershavetheabilitytophosphorylatethe3-hydroxylgroupofphosphoinositides[9].Theycouldbegenerallyclassifiedintothreeclassesacc
5、ordingtotheirprimarystructure,regulation,andinvitrolipidsubstratespecificity[34].ClassIPI3Ksareheterodimerscontainingaregulatorysubunitandacatalyticsubunit,whichmightbeinvolvedinmalignanttransformationinmanydifferentcancertypes.ThegenesofPIK3R1,PIK3R2andPIK3R3encode
6、theregulatorysubunit,namelyp85(α,?andγ)[38].p110isthecatalyticsubunitofclassIAPI3K.ThefunctionofPI3Kenzymesismainlydependedonit.Therearefourisoformsofp110:α,?,γandδ,whichareencodedbythegenesofPIK3CA,PIK3CB,PI3KCGandPIK3CD,respectively.Amongtherest,p110-αisinvolvedin
7、thegrowthofcellandistheisoformwhichisoftenoutofcontrolundercancerstate.Inaddition,classIIPI3Kenzymesaremonomericandinvolvedincellsurfacetrafficking,whereasclassIIIPI3Kenzymesareimplicatedintheregulationofautophagy[38].ACTIVITYCONTROLTheclassIAPI3Kenzymecomplexisclos
8、elyassociatedwithphosphotyrosineresiduesontheintracellularmembraneportionofRTKs.Undernormalstate,p85locksthecatalyticsiteofp110subunit.Onc
