Cellulartransformationisaccompaniedbymanycellularchanges,includinguncontrolledproliferation,lossofthedifferentiatedcellmorphology,andinvasionoftheextracellularmatrix.Degradationoftheextracellularmatrixisakeycomponentoftumorcellinvasionintosurroundingtissues.Matrixmetalloproteinases(MMPs)areaclassofproteasessecretedbytumorcells,degrADIngtheproteinsoftheextracellularmatrixandallowingmetastasis.DruginhibitorsofMMPsareonestrategytocontrolcancerandblockmetastasis.Insearchingforgenesthatreversetheroundedmorphologyoftransformedcellsinculture,RECKwasidentified(reversion-inducing,cysteine-richproteinwithKazalmotifs).RECKisamembrane-anchoredinhibitorofmatrixmetalloproteinases,inhibitingMMP-2,MMP-9andMT1-MMP.TheprocessingofMMPstotheiractiveformoccursattheplasmamembrane,makingthelocalizationofRECKatthemembraneakeytoitspotentactivityasaninhibitorofMMPactivity.SolublesecretedMMPinhibitorshavealsobeenidentified,TIMPs,whichappeartobelessactiveatinhibitingMMPsandevenperhapstobeessentialforMMPmaturation.TheinhibitionofMMPsbyRECKinhibitsinvasionoftissues,metastasisandtumorangiogenesis,andisessentialfornormaldevelopment.Inadditiontoplayingaroleintissueinvasionincancer,theactivityofMMPsinangiogenesis,inflammation,anddevelopmentisregulatedbyinhibitorssuchasRECKandTIMPs.RECKexpressionisinhibitedbyras,suggestingonecomponentbywhichrasinducestransformation.HighlevelsofRECKexpressionintumorsiscorrelatedwithcancerpatientsurvivalandoverexpressionofRECKmayofferatherapeuticstrategyforthecontrolofcancer.

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REFERENCES:FurumotoK.etal.(2001)RECKgeneexpressioninhepatocellularcarcinoma,Correlationwithinvasion-relatedclinicopathologicalfactorsanditsclinicalsignificance.Hepatology,33,189-195.Oh,J.etal.(2001)Themembrane-anchoredMMPinhibitorRECKisakeyregulatorofextracellularmatrixintegrityandangiogenesis.Cell107,789-800SasaharaR.M.,TakahashiC.andNodaM.(1999)InvolvementoftheSp1siteinras-mediateddownregulationoftheRECKmetastasissuppressorgene.Biochem.Biophys.Res.Commun.,264,668-675.SkilesJW,GonnellaNC,JengAY.(2001)Thedesign,structure,andtherapeuticapplicationofmatrixmetalloproteinaseinhibitors.Curr.Med.Chem.8(4),425-74Takahashi,Cetal.(1998)Regulationofmatrixmetalloproteinase-9andinhibitionoftumorinvasionbythemembrane-anchoredglycoproteinRECK.Proc.Nat.Acad.Sci.95,13221-13226Vu,T.H.andWerb,Z.(2000)Matrixmetalloproteinases,effectorsofdevelopmentandnormalphysiology.GenesDev.14,2123-2133.WeaverVM(2002)Membrane-associatedMMPregulators:novelcelladhesiontumorsuppressorproteins?Dev.Cell.2(1),6-7

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