Seeonlineversionforlegendandreferences.550Cell133,May2,2008©2008ElsevierInc.DOI10.1016/j.cell.2008.04.023SnapShot:PTENSignalingPathwaysArkaitzCarracedo,LeonardoSalmena,andPierPaoloPandolfiBethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,MA02115,USA550.e1Cell133,May2,2008©2008ElsevierInc.DOI10.1016/j.cell.2008.04.023SnapShot:PTENSignalingPathwaysArkaitzCarracedo,LeonardoSalmena,andPierPaoloPandolfiBethIsraelDeaconessMedicalCenter,HarvardMedicalSchool,Boston,MA02115,USAThePTEN(phosphataseandtensinhomologdeletedonchromosome10)geneencodesaplasmamembranelipidphosphatasethatisrecurrentlylostinvarioushumancancers.HeterozygousmutationofPTENiscausativeforfamilialdiseasesincludingCowdensyndrome,whichischaracterizedbymultiplehamartomas,developmentaldefects,andincreasedcancersusceptibility.Themajortumor-suppressiveactivityofPTENisattributedtoitsabilitytohydrolyzethe3′phosphateofphosphoinositidesattheplasmamembraneandtherebynegativelyregulatephosphoinositide3-kinase(PI3K)signaling,apromoterofcellgrowthandsurvival.Inmousemodels,Ptenishaploinsufficientfortumorsuppression.ProgressivereductionofPtendoseisalsoassociatedwithmoreaggressivecancersinthemouse,leadingtothenotionthatsubtlevariationsinPtenlevelscouldhavecriticalconse-quencesfortumorprogression.Indeed,inadditiontothelossofPTENfunctionthroughgeneticalterationsatthe10q23locus,emerginglinesofevidencedemonstratethatPTENistightlyregulatedbytranscriptional,posttranscriptional,andposttranslationalmechanisms.RecentstudiesreportthatPTENhastumor-suppressivefunctionsfromwithinthenucleus,includingtheregulationofchromosomalstability,theDNArepairresponse,andthecellcycle.AberrantcytoplasmiclocalizationofPTENisassociatedwithcancerprogression,suggestingthatthepresenceofPTENinthenucleusisrequiredforitstumor-suppressiveactivity.HowPTENgetsinandoutofthenucleusisstillnotcompletelyunderstood.Nuclearpore-mediatedimportaswellasthemonoubiquitinationofPTENcanmodulateitssubcellularcompartmentalization,andgermlinemutationsofresiduestha...
