Article

InteractionproteomeofhumanHipposignaling:modularcontroloftheco-activatorYAP1

SimonHauri1,2,AlexanderWepf3,AudreyvanDrogen1,MarkkuVarjosalo1,4,NicTapon5,RuediAebersold1,2,6&MatthiasGstaiger1,2,*

Abstract

Tissuehomeostasisiscontrolledbysignalingsystemsthatcoordi-natecellproliferation,cellgrowthandcellshapeuponchangesinthecellularenvironment.Deregulationoftheseprocessesisassoci-atedwithhumancancerandcanoccuratmultiplelevelsoftheunderlyingsignalingsystems.Togainanintegratedviewonsignalingmodulescontrollingtissuegrowth,weanalyzedtheinter-actionproteomeofthehumanHippopathway,anestablishedgrowthregulatorysignalingsystem.Theresultinghigh-resolutionnetworkmodelof480protein-proteininteractionsamong270networkcomponentssuggestsparticipationofHippopathwaycomponentsinthreedistinctmodulesthatallconvergeonthetranscriptionalco-activatorYAP1.OneofthemodulescorrespondstothecanonicalHippokinasecassettewhereastheothertwobothcontainHippocomponentsincomplexeswithcellpolarityproteins.Quantitativeproteomicdatasuggeststhatcomplexfor-mationwithcellpolarityproteinsisdynamicanddependsontheintegrityofcell-cellcontacts.Collectively,oursystematicanalysisgreatlyenhancesourinsightsintothebiochemicallandscapeunderlyinghumanHipposignalingandemphasizesmultifacetedrolesofcellpolaritycomplexesinHippo-mediatedtissuegrowthcontrol.

KeywordsAP-MS;cellpolarity;Hipposignaling;modularity;proteincomplexanalysis

SubjectCategoriesNetworkBiology;SignalTransduction

DOI10.1002/msb.201304750|Received31July2013|Revised13November2013|Accepted20November2013MolSystBiol.9:713

Introduction

Developmentofmetazoantissuesandorgansdependsontightcontrolofproliferation,cellgrowthandprogrammedcelldeathinresponsetoextracellularandintracellularsignals.Geneticand

biochemicalexperimentsoriginallyperformedinDrosophilamelanogasterledtothediscoveryoftheHippo(Hpo)pathway,acon-servedsignalingcascadethatcontrolstissueandorganhomeostasisinmetazoans.Itscorecomponentsareconservedinhumansandhavebeenimplicatedinavarietyofhumancancers(Pan,2010;Zhaoetal,2010;Harveyetal,2013).TheseincludetheSTE20kinasesMST1andMST2(orthologsoftheDrosophilaHpokinase)whichbindtoSAV1(WW45),theAGCkinaseLATS1(Largetumorsuppressorhomolog1)anditsassociatedscaffoldproteinsMOB1A/B(Harvey&Tapon,2007;Pan,2007).DownstreamofthiskinasecascadearetheWW-domain-containingtranscriptionalco-activatorsYAP1andTAZ(Dongetal,2007;Zhaoetal,2007;Leietal,2008)thetwomajoreffectorsoftheHpopathway.ActiveMST1/2incomplexwithSAV1phospho-rylatesLATS1/2,whichinturnstimulatesLATS-MOBcomplexforma-tionandactivationofLATSkinaseactivity.ActiveLATS1/2kinasesphosphorylateandinactivateYAP1andTAZthrough14-3-3protein-mediatedcytoplasmicsequestration(Dongetal,2007;Guoetal,2007;Zhaoetal,2007;Leietal,2008;Okaetal,2008;Zhangetal,2008).WhentheHpopathwayisinactive,hypo-phosphorylatednuclearYAP1andTAZbindtotheTEAdomaintranscriptionfactors(TEAD1/2/3/4)todriveexpressionofpro-growthandanti-apoptoticgenes(Wuetal,2008;Zhaoetal,2008).

WhilethesignalingmechanismfortheHpocoremoduleiswell-established,ourunderstandingofthephysiologicalcues,signalingcomponentsandmechanismsthatcontroltheactivationandrepres-sionofthehumanHpopathwayisstillquitelimited.RecentgeneticdatafromDrosophilaandbiochemicalanalysisinhumancellssuggestthatHposignalingislinkedtocellpolarity,thecytoskeletonandcelljunctions(Genevet&Tapon,2011;Schroeder&Halder,2012).However,themolecularcomplexesthattransmitpolarityandcytoskeletalsignalstotheHpocoremodulesarejustbeginningtoemergeandthereisdebateastowhetherthesearedependentonthecorecascadeoriftheyactdirectlyonYAP1.

Sincemostproteinsexerttheirfunctioninthecontextofspecificproteincomplexes,thecharacterizationofcomplexesinvolvinggeneticallydefinedHpocomponentsturnedouttobeaparticularlysuccessfulapproachtouncovernovelregulatorsandmechanisms

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€rich,Zu€rich,SwitzerlandInstituteofMolecularSystemsBiology,ETHZu

€rich,Zu€rich,SwitzerlandCompetenceCenterforSystemsPhysiologyandMetabolicDiseases,ETHZu

AnalyticaMedizinischeLaboratorienAG,Zurich,Switzerland

InstituteofBiotechnology,UniversityofHelsinki,Helsinki,FinlandCancerResearchUK,LondonResearchInstitute,London,UK

€rich,Zu€rich,SwitzerlandFacultyofScience,UniversityofZu

*Correspondingauthor.Tel:+41446337149;Fax:+41446331051;E-mail:gstaiger@imsb.biol.ethz.ch

ª2013TheAuthors.ThisisanopenaccessarticleunderthetermsoftheCreativeCommonsAttributionLicense,whichpermitsuse,distributionandreproductioninanymedium,providedtheoriginalworkisproperlycited.

MolecularSystemsBiology9:713|2013

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