FourdifferentmembersoftheSproutyproteinfamilyblockthecellularproliferationanddifferentiationinducedbyseveraldifferentgrowthfactors,includingEGFandFGF.OnemechanismbywhichSproutyproteinsinhibitsignalingisthroughbindingtoGrb-2,asignalingintermediarybetweenthetyrosinekinasegrowthfactorsandtheRas/mapkinasepathway.BindingofSproutytoGrb-2preventsGrb-2andSos-1frominteractingwithdownstreamsignalingfactorsthatactivateRasandmapkinases,includingRas,Raf-1,Mek1,Erk1/2anddownstreamtranscriptionfactors.TheactionofSproutyasaninhibitorofthispathwayrequiresSproutyphosphorylationandmembranelocalization,atthesiteofthefactorsitinteractswith.TheinhibitionofgrowthfactorsignalingbySproutyisspecifictotheRaspathwaysincethePI3KinasepathwayresponsIBLeforcellsurvivalsignalsfromgrowthfactorreceptorsisnotinhibitedbySprouty.Tyrosinekinaseactivityofgrowthfactorreceptorsisalsonotaffected.ThemechanismbywhichSproutyinhibitsRasactivationmaybebyblockingthenucleotideexchangeactivityofSos.SproutyexpressionisinducedbygrowthfactorreceptoractivationofRassignaling,providedaself-regulatoryfeedbackinhibitionmechanismthatregulatesgrowthfactorsignalingthroughRas.InadditiontoblockingtheRaspathway,Sproutyalsoinducesproteintyrosinephosphatase1Bactivity.ActivationofPTP1BbySproutyisresponsiblefortheinhibitionofcellularmigrationthatSproutycauses,butisnotinvolvedinregulationofcellularproliferation.Whileblockingreceptortyrosinekinasesignaling,atleastonememberoftheSproutyfamily,Sprouty-2,alsoactsbyonemechanismtostimulateEGFreceptorsignaling.CbltargetstheEGFreceptorfortaggingwithubiquitinandproteolyticdestruction.Sprouty-2bindstoCblandblockstheubiquitinationanddestructionoftheEGFreceptor,increasingEGFsignaling. Contributor:KosiGramatikoff,PhD REFERENCES:EganJE,HallAB,YatsulaBA,Bar-SagiD.ThebimodalregulationofepidermalgrowthfactorsignalingbyhumanSproutyproteins.ProcNatlAcadSciUSA.2002Apr30;99(9):6041-6.FioriniM,AlimandiM,FiorentinoL,SalaG,SegattoO.Negativeregulationofreceptortyrosinekinasesignals.FEBSLett.2001Feb16;490(3):132-41.Review.GlienkeJ,FentenG,SeemannM,SturzA,ThierauchKH.HumanSPRY2inhibitsFGF2signallingbyasecretedfactor.MechDev.2000Aug;96(1):91-9.GrossI,BassitB,BenezraM,LichtJD.Mammaliansproutyproteinsinhibitcellgrowthanddifferentiationbypreventingrasactivation.JBiolChem.2001Dec7;276(49):46460-8.ImpagnatielloMA,WeitzerS,GannonG,CompagniA,CottenM,ChristoforiG.Mammaliansprouty-1and-2aremembrane-anchoredphosphoproteininhibitorsofgrowthfactorsignalinginendothelialcells.JCellBiol.2001Mar5;152(5):1087-98.LeeSH,SchlossDJ,JarvisL,KrasnowMA,SwainJL.Inhibitionofangiogenesisbyamousesproutyprotein.JBiolChem.2001Feb9;276(6):4128-33.LimJ,WongES,OngSH,YusoffP,LowBC,GuyGR.Sproutyproteinsaretargetedtomembranerufflesupongrowthfactorreceptortyrosinekinaseactivation.Identificationofanoveltranslocationdomain.JBiolChem.2000Oct20;275(42):32837-45.LimJ,YusoffP,WongES,ChandramouliS,LaoDH,FongCW,GuyGR.Thecysteine-richsproutytranslocationdomaintargetsmitogen-activatedproteinkinaseinhibitoryproteinstophosphatidylinositol4,5-bisphosphateinplasmamembranes.MolCellBiol.2002Nov;22(22):7953-66.NiehrsC,MeinhardtH.Modularfeedback.Nature.2002May2;417(6884):35-6.Noabstractavailable.WongES,LimJ,LowBC,ChenQ,GuyGR.EvidencefordirectinteractionbetweenSproutyandCbl.JBiolChem.2001Feb23;276(8):5866-75.YigzawY,CartinL,PierreS,ScholichK,PatelTB.TheCterminusofsproutyisimportantformodulationofcellularmigrationandproliferation.JBiolChem.2001Jun22;276(25):22742-7.YigzawY,PoppletonHM,SreejayanN,HassidA,PatelTB.Protein-tyrosinePhosphatase-1B(PTP1B)MediatestheAnti-migratoryActionsofSprouty.JBiolChem.2003Jan3;278(1):284-8.YusoffP,LaoDH,OngSH,WongES,LimJ,LoTL,LeongHF,FongCW,GuyGR.Sprouty2inhibitstheRas/MAPkinasepathwaybyinhibitingtheactivationofRaf.JBiolChem.2002Feb1;277(5):3195-201.