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

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