membrane7788kk.com

ReviewWWdomaininteractionsregulatetheHippotumorsuppressorpathwayZSalah1andRIAqeilan*,1TheHippokinasepathwayisemergingasaconservedsignalingpathwaythatisessentialfororgangrowthandtumorigenesisinDrosophilaandmammalians.
Althoughthesignalingofthecorekinasesisrelativelywellunderstood,lessisknownabouttheupstreaminputs,downstreamoutputsandregulationofthewholecascade.
EnrichmentoftheHippopathwaycomponentswithWWdomainsandtheircognateproline-richinteractingmotifsprovidesaversatileplatformforfurtherunderstandingthemechanismsthatregulateorgangrowthandtumorigenesis.
Here,wereviewrecentlydiscoveredmechanismsofWWdomain-mediatedinteractionsthatcontributetotheregulationoftheHipposignalingpathwayintumorigenesis.
Wefurtherdiscussnewinsightsandfuturedirectionsontheemergingroleofsuchregulation.
CellDeathandDisease(2011)2,e172;doi:10.
1038/cddis.
2011.
53;publishedonline16June2011SubjectCategory:CancerThemechanismscontrollingmammalianorgansizehavebeentheinterestofscientistsforalongtime.
Duringthelastfewyears,immenseprogresshasbeenmadeindecipheringthesemechanismsandtheirimplicationsindiseasedevelopment,includingcancer.
Theregulationoforgangrowthiscontrolledbythenumberofcelldivisionsandtherateofcelldeath.
Theseprocessesregulatetissuehomeostasisandmaintaintheproperfunctionoforgans.
TherecentdiscoveryoftheHippopathwayasakeyregulatoroforgangrowthinfruitieshasgenerateddeeperinsightsintothemechanismoforgansize.
1,2Moreover,deregulationoftheHippopathwaycomponentsinmanydifferenttypesofcancersfurthersitscriticalroleintumorigenesis(reviewedinZhaoetal.
3).
AlthoughsignicantprogresshasbeenmadeinunderstandingthecoresignalingcascadeoftheHippopathway,muchlesshasbeenachievedinexploringtheregulationofthepathway.
Recently,muchattentionwasgiventotheunusualabundanceofWWmodulesandtheirinteractingcognateswithinsignalingmoleculesoftheHippopathway.
4,5ThisprevalenceofWWdomain-mediatedcomplexesintheHippopathwayperhapsfacilitatesitsmolecularanalysis,aidsinpredictionofnewpathwaycomponentsanduncoversnewmechanismsofregulation.
WWDomainsManyofthesignalingproteinscontainmodulardomainsthatfacilitateprotein-proteininteractions,oftenthroughtherecognitionofspecicandshortpeptidemotifsintheirbindingpartners.
Theseinteractionsaremostlyregulatedbypost-translationalmodications,forexample,phosphorylation.
Specicprotein-proteininteractionscantherebycontrolthesubcellularlocalization,enzymaticactivityandtheassemblyofmulti-proteincomplexes,thusallowingtheowofinforma-tionthroughsignalingpathways.
OnesuchexampleistheWWdomainmodules'interactions.
WWdomain,thesmallestmodulethatnaturallyoccurs,consistsofB35–40aminoacidresidues,includingtwohighlyconservedtryptophan(W)residuesseparatedby20–23aminoacidsinthepolypeptidechain.
6–8ThesetwoWaminoacidsgivethedomainitsname,WWdomain.
Originally,WWdomainswereidentiedthroughdetailedcharacterizationoftheYes-associatedprotein(YAP)basedoncomputer-aidedanalysisofimperfectlyrepeatedsequencesinthemouseisoformofYAP,andinyeastfactorRSP5.
7,8FunctionalscreenofacDNAexpressionlibraryidentiedthersttwoputativeWWdomainligands,WBP1and2.
9,10Todate,WWdomainsconstituteveclassesdependingonthecontentoftheircognateproline-richbindingmotifs(PRM).
11–14ThemostabundanttypeofWWdomainsareclass-IWWdomains,whichbindtoPPxYmotifs,wherePisproline,xisanyaminoacidandYistyrosine.
AlthoughWWdomainswithindifferentproteinsmighthaveaverysimilarstructure,theyhavedifferentialbindingtovariousligands.
Moreover,differentWWdomainsfallinginatandemrepeatmannerhavedifferentReceived28.
3.
11;revised28.
4.
11;accepted29.
4.
11;EditedbyGMelino1TheLautenbergCenterforGeneralandTumorImmunology,DepartmentofImmunologyandCancerResearch-IMRIC,TheHebrewUniversity–HadassahMedicalSchool,Jerusalem,Israel*Correspondingauthor:RIAqeilan,TheLautenbergCenterforGeneralandTumorImmunology,DepartmentofImmunologyandCancerResearch-IMRIC,TheHebrewUniversity–HadassahMedicalSchool,POBox12272,Jerusalem91120,Israel.
Tel:97226758609;Fax:97226424653;E-mail:aqeilan@cc.
huji.
ac.
ilKeywords:WWdomain;Hippopathway;protein-proteininteraction;ITCH;LATS1Abbreviations:WBP1and2,WWdomainbindingprotein1/2;YAP,Yes-associatedprotein;PQBP1,polyglutaminetract-bindingprotein1;MST1/2,mammalianSTE20-likekinase1/2;LATS1/2,largetumorsuppressor,homolog1/2;PRM,proline-richbindingmotifs;Yki,Yorki;Sav,Salvador;Dchs,Dachsous;Ex,Expanded;Mer,merlin;TAZ,transcriptionalcoactivatorwithPDZbindingmotif;EMT,epithelial-to-mesenchymaltransition;CTGF,connectivetissuegrowthfactor;AMOTL1/2,angiomotin-likeproteins1and2;AMOT,Angiomotin;ASPP1/2,apoptosis-stimulatingproteinofp531and2;Dvl-2,dishevelled2;RUNX2,runt-relatedtranscriptionfactor2;ERBB4,erythroblasticleukemiaviraloncogenehomolog4Citation:CellDeathandDisease(2011)2,e172;doi:10.
1038/cddis.
2011.
53&2011MacmillanPublishersLimitedAllrightsreserved2041-4889/11www.
nature.
com/cddisbindingpropertiestodifferentproteins,suggestingthatWWdomainsbindtoavastrepertoireofdifferentproteinsandthattheymightbepartofcomplexesbridgingblocks.
15–17WWdomain-containingproteinsappeartobeveryimportantinhomeostasisastheyoccurinproteinsinvolvedinawidearrayofbiologicalprocessesincludingtranscription,apoptosis,differentiation,splicingandubiquitination.
Infact,thesedomainsgainedtheiressentialroleafterbeingshowntobeinvolvedinhumandiseasesincluding,Liddle'ssyndromeofhypertension,wheretheWWdomainligand(PPxYdomain)isdeletedormutated,18,19musculardystrophy,20,21Alzheimer's,22–24Huntington'sdiseases,25,26Golabi-Ito-Hallsyndromeofmentalretardation,inwhichthebindingofY65C-mutatedWWdomainofpolyglutaminetract-bindingprotein1(PQBP1)toitscognateproline-richligandsisabrogated,27andmorerecentlycancer.
3,28–30Moreover,WWdomain-containingproteinshavegainedfurtherinterestafterbeingidentiedintheHippotumorsuppressorpathway.
HippoTumorSuppressorPathwayThefactthatseparateWWdomainsfromthesameprotein,orcloselyrelatedproteins,canhavedifferentspecicitiesforproteinligands,andthatasinglepolypeptidecanbindmultipleclassesofWWdomainsthroughseparatePRMsuggestedthatWWdomainsprovideaversatileplatformtolinkindividualproteinsintophysiologicallyimportantnetworks.
16,17OnesuchimportantnetworkthathasreceivedmuchattentioninthelastfewyearsistheHippotumorsuppressorpathway.
TheHippopathwayisahighlyconservedpathwaythatregulatestissuegrowthandorgansizebyregulatingcellgrowth,proliferation,differentiationandapoptosis.
3,29Inactivationormutationsofsomecomponentsofthepathwaywereidentiedindifferenttypesofcancer.
3,29,31TheHippopathwayiscomposedofakinasecascadecorethatincludesMST1/2serine/threoninekinase(orthologofHpo),WW45scaffoldprotein(Sav),MOB(Mts)andLATS1/2kinases(Wts)(Figure1).
Thiskinasecascadeisactivatedbyamechanismthatisnotyetfullyestablished,althoughsomeproteinswereidentiedtofeedintothecoreHippokinasecassette-likeFat,Dachsous(Dchs),Kibra,Expanded(Ex),Merlin(Mer)andothers(reviewedinGruscheetal.
32).
ActivationofthecorecascadeleadstophosphorylationofYAP33–35andTAZ36(Ykiinies)leadingtotheirsequestrationinthecytoplasm,preventingtheirtranslocationtothenucleusandbindingtoTEADtranscriptionfactor,therebyinhibitingtranscriptionofdownstreamtargetgenesimplicatedinproliferation,anti-apoptosisandepithelial-to-mesenchymaltransition(EMT).
37AuniquefeatureoftheHippopathwayisthehighprevalenceofWWdomain-mediatedcomplexes,denedrecentlyasWWmodularityoftheHippopathway.
4TheWWdomaincontainingproteinsoccuratdifferentlevelsoftheHippopathway.
InthecorecomponentsoftheHippopathwayinbothDrosophilaandmammals,theinteractionsaremediatedviaPPxYmotifsandWWdomains.
InDrosophila,HpoandWtseachcontainPPxYmotifs,andSavcontainstwoWWdomains.
Inmammals,thecorecassettealsocontainseitherPPxY/Fmotifs(Table1),asinthecaseofLATS1/2andMST1/2,orWWdomains,asincaseofWW45.
4Inaddition,thenucleareffectorsofthepathway,YkiiniesandYAPorTAZinmammals,functionthroughWW–PPxYinteraction.
Indeed,ithasalsobeenshownthattheWWdomainsofYAParecrucialforYAPtranscriptionalco-activationfunction+ProliferationgenesAnti-apoptoticgenesEMT-relatedgenesUBMST1/2LATS1ITCHPTEADYAPYAPProteasomaldegradation14-3-3PYAP-TRCPPYAPUBFigure1ITCHregulatestheHippopathwaybydegradingLATS1.
TheE3ubiquitinligaseITCHinteractswithLATS1byWWdomain–PPxYmotif-dependentmannerleadingtoubiquitinationandprotaesomaldegradationofLATS1.
ThisresultsinreducedYAPS127phosphorylation,thuslesscytoplasmicsequestrationbybindingto14-3-3protein,reducedYAPprotaesomaldegradationmediatedbyb-TRCPE3ligaseandconsequentlyenhancedYAPtranslocationtothenucleustomediateYAPdependentco-activationofTEAD-responsivegenes,includingthoseimplicatedinproliferation,anti-apoptosisandEMT.
Uponactivationofthepathway,ITCH–LATS1interactionisenhancedleadingtomoreefcientdegradationofLATS1attenuatingitsphosphorylationactivityofYAP.
Thisfunctionalassociationmighthavearoleinne-tuningtheoutcomeoftheHippopathwayandcouldbederegulatedinspecicsettingsuchasintumorigenesis.
Table1ExamplesofWWdomainandPPxY-containingproteinsintheHippopathwayWWDomainproteinsYAP1/21-WWand2-WW3,33–35,37,46TAZ1-WW29,36,59KIBRA2-WW38–40WW45(SAV1)2-WW60,61ITCH4-WW42,43PPXY/F-containingproteinsDCHS1/24-PPxFand2-PPxFa4,32,62FT1/2PPxYandPPxFa4,63–65CRB1/21-PPxYand2-PPxFa4,66,67MST1/21-PPxFand1-PPxFa4,60,68,69LATS1/22-PPxYand1-PPxY34,35WBP23-PPxY47,48AMOT2-PPxY49,51AMOTL1/22-PPxY50ASPP1/21-PPxYand1-PPxFa4,52,53,70P731-PPxY28,30,44,45ERBB43-PPxY28,30,71–73SMAD11-PPxY74RUNX21-PPxY28,30,59,75DVL21-PPxY76aPPxFmotifwassuggestedbySudolandHarvey4asapotentialWWdomainligandbasedoninvitroresults.
WWdomainproteinsregulatetheHippopathwayZSalahandRIAqeilan2CellDeathandDiseasedownstreamoftheHippopathway.
37NotonlydothecorecomponentsorthedownstreameffectorscontainWWdomainsbutalsoseveralupstreamregulatorsoftheHippopathway,inbothDrosophilaandmammals,containeitherWWorPPxYmotifs.
Forexample,theWWdomainproteinKibraisaHipposignalingcomponentupstreamofHpo/MSTandMerlin.
38,39ThismodularityintheHippopathwaymightintendthatthispathwayisregulatedbyWWdomain-containingproteinsatdifferentlevelsinthepathway,fromthemediatorsdowntothecorecomponentsandeffectors.
WWDomainProteinsRegulateMembersoftheHippoPathwayWWdomainsofkibraregulateHippopathwayproteins.
Recently,differentreportshavedescribedgrowingevidenceofanumberofproteinsthatregulatethecorecomponentsoftheHippopathway.
SomeoftheseproteinscanbebroadlytermedupstreamHippopathwayregulatorsandincludeproteinsthatsignalviatheatypicalcadherin,Fat,whichfunctionsasatransmembranereceptorfortheHippopathway.
32Additionally,theKibra–Expanded–Merlincomplexlinkstheapicalmembranetothecoreofthepathwayproteinsandtheapicobasalpolarityproteins.
32Theseupstreamregulatorsmakedifferentphysicalinteractionswiththepathwaytomanipulateitsfunctions.
OneexampleoftheseinteractionsistheWWdomain–PPxYmotifinteractioninducedbyKibra.
Recently,ithasbeenshownthatdifferentnullmutantsoftheKibrageneareassociatedwithincreasedcellnumberleadingtotissueovergrowth.
Ontheotherhand,Kibraoverexpressingclonescontainfewercellsthancontrolclonesassociatedwithinducedapoptosis.
40KibrafunctionsprimarilyupstreamofMerandcontributestoMer-independentregulationofYkiactivity.
ThiseffectonMerseemedtobemediatedbyphysicalinteractionofthetwoproteins.
ThisinteractionwasfoundtobeindependentoftheWWdomainsofKibra.
40OntheotherhandLingXiaoetal.
41showedthattheKibraWWdomainsareessentialforKibra–LATSinteractionandregulationofLATS1/2functionsinthecontextofthemammalianHippopathway.
Uponitsexpression,KibraactivatesLATS1/2asrevealedbyitsincreasedphos-phorylation,leadingtoincreasedphosphorylationoftheultimateeffectorofthepathway,YAP.
41NotonlywasKibrashowntoenhanceLATSfunctionbutitwasalsoshowntoberesponsibleforincreasedLATS2proteinlevels.
Kibra-LATS2associationincreasesLATS2half-life,atleastinpart,byinhibitingLATS2ubiquitinationanditsproteasomaldegradation.
41Implicationofthisfunctionalinteractionontumorigenesisinvivoisstilltobedetermined.
WWdomainsofITCHregulatesLATS1stability.
Re-cently,tworeportsidentiedtheE3ligaseresponsiblefortheproteasomaldegradationofLATS1.
Therst,comingfromourlab,identiedITCHasaWWdomain-containingproteinthatregulatesthestabilityofLATS1usingWWdomainarrays.
42ThesendingswereconrmedlaterbyanothergroupthatutilizedSILAC(StableIsotopeLabelingwithAminoAcidsincellculture).
43Botharticlescametothesameconclusion,identifyingLATS1asatargetoftheE3ligaseITCH(Figure1).
Inourwork,wedemonstratedthatITCH,mostlyviaitsrstWWdomain,interactswiththePPxYmotifsofLATS1andenhancesitsubiqitinationandproteasomaldegradation.
42Ofnote,ITCHinteractionwithLATS1wasincreaseduponactivationoftheHippopathwayeitherbyMST2overexpressionorbyhigh-celldensityculture.
ThisinteractionwasassociatedwithenhanceddegradationofLATS1andsuggestthatITCHmightspecicallytargettheactivatedformofLATS1.
42Expressionofakinase-deadmutantofMST2(MSTD-KD),whichisincapableofphos-phorylatingandactivatingLATS1,indeedrescued,atleastinpart,ITCH-mediatedLATS1degradation(Unpublisheddata,SalahandAqeilan).
WhetherITCHexpressionand/orfunctionisaffectedbyLATSkinasesisstillanopenquestion.
Collectively,thismaysuggestthatITCHmightfunctionasane-tuningregulatoroftheHippopathwayunderphysiologicalconditions.
ITCH-mediatedLATS1degradationisalsoaccompaniedbyreducedYAPphosphorylationonSer127,mildYAPaccumu-lationinthenucleusandincreasedco-activationfunctionofTEAD-responsivegenes.
42AsYAPphosphorylationhasbeenshowntotriggeritsdegradationbySCF-(bTRCP)E3ubiquitinligase,ourresultsmaysuggestthatITCHexpressionmightsignalforYAPstabilizationandTEADco-activation.
42ThendingsbySalahetal.
42furtherdemonstratedthatLATS1degradationbyITCHenhancesEMTinHeLaandMCF10Acells,phenocopyingoverexpressionofYAP.
1,3IncreasedlevelsofYAP-relatedEMTgenes,includingCTGFandbronectin,andincreasedcellularmigrationandinvasionarehallmarksofITCHoverexpression.
NotonlydidthecellsshowmoreEMTphenotypesbutalsoITCH-manipulatedcellsaremoretumorigenicbothinvitroandinvivo.
ThendingsofHoetal.
43alsoconrmedthatITCHnegativelyregulatesLATS1levelandfunctionasrelatedtocellproliferationandapoptosisinthesamewayasdemonstratedearlier.
42BecauseITCH,asanE3ligase,targetsmanysubstrates,44,45itispossibletospeculatethatthephenotypesobservedafterITCHoverexpressionarerelatedtotheregulationofthedifferenttargetsinagivencontext.
Nevertheless,thesephenotypeswererescued,atleastinpart,inoursettingswhenmanipulatingLATS1expression,suggestingthatLATS1isacriticaltargetofITCH-mediatedtumorgrowthandprogressionbyregulatingtheHippopathway.
AsdifferentWWdomainproteinsmaysharecommontargets,itislikelytoassumethatchangingthelevel,stabilityorsubcellularlocalizationofoneWWproteinwouldalterthefunctionandoutcomeofWWdomaintargets,dependingonthecellularcontextortheexpressionofthedifferentproteins.
17,30Forexample,p73isacommonligandforITCHandYAP.
Ononehand,ITCHdegradesp73,44whileontheotherhanditleadstoenhancedYAPtranslocationtothenucleustopromoteTEAD-dependenttranscription.
3Inaddi-tion,YAPisanimportantco-factorforp73-dependenttranscriptionalactivityandexertsatumorsuppressorroleinthiscontext.
45Therefore,ITCHoverexpressionmightserveasamolecularswitchbetweenopposingYAPfunctions.
WhetherYAPrelocatesbetweenp73/YAPtargetsandTEAD/YAPtargetsinresponsetoITCHistobedeterminedinfutureWWdomainproteinsregulatetheHippopathwayZSalahandRIAqeilan3CellDeathandDiseasestudies.
ItwouldalsobenecessarytodeterminewhethertargetedmanipulationofWWdomainproteinsortheirinteractingpartnersintheHippopathwaywouldtilttheoutcomeoforgansizeand/ortumorigenicity.
AsITCHbehavesasaproto-oncogene,itmightalsocontributetotheobserveddownregulationofLATS1levelsincancer,andpossiblyothercomponentsoftheHippotumorsuppressorpathway.
Insummary,thesendingssuggestthatnovelWWdomainscouldregulatethecorecomponentsoftheHippopathwaytherebyaffectingtumorigenesisand,perhaps,organgrowth.
PPxY-containingproteinsregulateeffectorsoftheHippopathway.
AnotherlevelwhereWWdomainsappeartoregulatetheHippopathwayisontheleveloftheeffectors,YAPandTAZ.
Indeed,LATSproteins,viatheirPPxYmotifs,havebeenshowntobindtoWWdomainsofYAPleadingtoYAPphosphorylation,sequestrationinthecytoplasmandinactivation.
33,34,46ThisleadstoreduceYAP-inducedEMTphenotypesandisassociatedwithreducedtumor-igenicity.
1,34Infact,itwasshownthattheWWdomainofYAPhasacriticalroleininducingasubsetofYAPtargetgenesindependentof,orincooperationwith,TEAD.
37Inaddition,mutagenesisoftheWWdomainsdiminishestheabilityofYAPtostimulatecellproliferationandoncogenictransformation.
37Insupportofthisnotion,tworecentpapersshowedthatWWdomain-mediatedinteractionwithWBP2isimportantforthephenotypesinducedbybothYki47andTAZ.
48Intherstwork,Zhangetal.
47reportedthatYki,viaitsWWdomain,bindstothePPxYmotifsofWbp2.
ImportantlythisinteractionleadstoincreasedYkitranscriptionalco-activationfunctionandisassociatedwithYki-driventissueovergrowth.
KnockdownofWbp2expressionbyRNAiinawts-decientbackgroundreversedthelethalovergrowthphenotypesinwtsnullorganisms,suggestingthatYkifunctionismediatedbyWbp2.
47Inmammaliancells,TAZ'sWWdomains'interactionwithPPxYmotifsofWBP2suggestedanindispensableroleofWBP2inTAZtransformingability.
48AlthoughknockdownofWBP2suppressedTAZ-driventransformation,itsoverexpressionenhancedthistransformation.
48Recently,thePPxY-containingAngiomotin(AMOT)-likeproteins1and2(AMOTL1/AMOTL2)wereidentiedasregulatorsofthedownstreameffectorsoftheHippopathway,YAPandTAZ.
49–51ThreearticleshighlightthesignicanceofthisinteractionandshedlightontheroleofAMOTcelljunctionproteinsinregulatingYAPandTAZfunction.
49–51TheseproteinswerefoundtospecicallyinteractwithYAPinaWWdomain-PPxYmotif-dependentmanner.
ThisinteractionwasfoundtobesufcienttosequesterYAPandTAZinthecytoplasm,independentoftheirphosphorylationstatus.
Specically,AMOTexpressionleadstoYAPlocalizationatthetightjunctionandcellmembrane,preventingYAPnucleartranslocation.
51Moreover,itwasshownthatknockdownofAMOTL2phenocopiesYAP-inducedEMTinMCF10Acells.
51Consideringthisscenario,lossoftightjunction-localizedYAPandTAZincreasedtheirnuclearlocalizationandwasaccompaniedbyinductionofYAP/TAZtargetgeneexpres-sion,andmostimportantly,transformationandlossofcellcontactinhibition.
Furthermore,AMOTL2knockdown-depen-dentphenotypeswereblockedbysimultaneousknockdownofYAPandTAZ,demonstratingthattheAMOTfamilyproteinsarenewcomponentsoftheHippopathwaywithtumor-suppressingpotential,indicatinganewmodeofYAPandTAZregulation.
51Inadifferentmanner,WWdomain-PPxYmotifinteractionwasinvolvedintheregulationofthedownstreameffectorsoftheHippopathwaybyinvolvingmorethantwoproteins.
Forexample,ASPP2wasshowntostimulateTAZdepho-sphorylation,partlybypromotingtheinteractionbetweenTAZandPP1;thisfunctionofASPP2requirestheTAZWWdomain.
ASPP2–TAZinteractionpromotesTAZnuclearlocalizationandTAZtargetgeneexpression.
52Inanotherexample,itwasshownthatASPP1wasabletoinhibitYAP/TAZinteractionwithLATS1,leadingtoenhancednuclearaccumulationofYAP/TAZandYAP/TAZ-dependenttranscriptionalregulation.
ThisresultsinYAP/TAZactivationandthusinhibitsapoptosis,inpart,throughthedownregula-tionofBimexpression,leadingtoresistancetoanoikisandenhancedcellmigration.
53ConcludingRemarksandFutureDirectionsTheuniquefeatureoftheHippopathwayoverothersignalingpathwaysisitshighmodularityrepresentedbythegreatprevalenceofWW–PPxYinteractions,whichmightstronglysuggestthatotherWWdomainandPPxYmotif-containingproteinsregulate,orarepartof,theHippopathway.
ThestudyofWWdomainsandHippopathwayinrecentyearsfurtherhighlightedimportantaspectsofWWdomainproteinsignalingincludingdimerizationcapability,regulationofWWdomain-PRMinteractionandnetworking(reviewedinSudol5).
WWdomainsarepresentinawidevarietyofcellularproteinsincludingE3ligases,co-activators,co-repressorsandadapterproteinsthatcouldpotentiallyregulatemembersoftheHippopathway.
Takingintoconsiderationtheimportantroleofthispathwayintissuegrowthandhomeostasis,furthereffortsshouldbeinvestedinidentifyingnewregulatorsandcompo-nentsofthispathway.
TheuseofGFP-expressingtumorcellsinfreshtissueorliveanimalsshallfacilitatebetterchara-cterizationoftheHippopathwayproteinsandtheirrole,bothinvitroandinvivo,intumorinitiationandprogression.
54–57ExpansionofthisinformationmayaidindevelopingnewtherapeuticstrategiesbasedontheWWdomaininteractionsinthispathway.
Infact,thedesignofinhibitorsoractivatorsofWWdomainsignalingcomplexesintheHippopathwaycouldbefacilitatedbytheconsiderabledataavailableontheWWdomainstructure,themechanismofinteractionwithitsrigidligands,andthecomplexesitforms.
58OwingtothefactthattheWWdomainanditsligands'coremotifsarerelativelyshort,itmightbepossibletousesmallmoleculesthatfunctionasactivatorsorinhibitorsfortheHippopathwaysignalingproteins;thatis,smallchemicals/peptidesthatinhibitYAPandTAZoncogenicfunction.
However,beforethinkingabouttherapeuticstrategiesbasedonWWdomaininteractions,furtheranalysisoftheWWdomain-mediatedcomplexesintheHippopathwaymustbeelucidatedtobetterdesignnoveltherapeuticstrategiesformalfunctionsthatinvolvetheWWdomain.
WWdomainproteinsregulatetheHippopathwayZSalahandRIAqeilan4CellDeathandDiseaseConictofInterestTheauthorsdeclarenoconictofinterest.
Acknowledgements.
WearegratefultoMsSherriCohenandMrsAlizaFormanforcriticalreadingofthemanuscript.
Weapologizetothosecolleagueswhoseworkwecouldnotcitebecauseofspacelimitation.
ThisworkwassupportedinpartbytheIsraeliScienceFoundationgrant(ISF#1331-08)andMarieCurie-EuropeanRe-integrationGrant(Project#224848)toAqeilanRIandIsraeliCancerResearchFund(ICRF)toSalahZ.
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