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• W2182560250 abstract "The glial cell line-derived neurotrophic factor (GDNF) family ligands (GFLs) are critical for nervous system development and maintenance.GFLspromotesurvivalandgrowthviaactivationofthereceptortyrosinekinase(RTK)Ret.Insympatheticneurons,theduration of Ret signaling is governed by how rapidly Ret is degraded after its activation. In an effort to elucidate mechanisms that control the half-life of Ret, we have identified two novel Ret interactors, CD2-associated protein (CD2AP) and Cbl-3. CD2AP, an adaptor molecule involvedintheinternalizationofubiquitinatedRTKs,isassociatedwithRetunderbasal,unstimulatedconditionsinneurons.AfterRet activationbyGDNF,CD2APdissociates.Similarly,theE3-ligaseCbl-3interactswithunphosphorylatedRetanddissociatesfromRetafter Ret activation. In contrast to their dissociation from autophosphorylated Ret, an interaction between CD2AP and Cbl-3 is induced by GDNF stimulation of sympathetic neurons, suggesting that CD2AP and Cbl-3 dissociate from Ret as a complex. In neurons, the overexpression of CD2AP enhances the degradation of Ret and inhibits GDNF-dependent survival, and gene silencing of CD2AP blocks Ret degradation and promotes GDNF-mediated survival. Surprisingly, Cbl-3 overexpression dramatically stabilizes activated Ret and enhances neuronal survival, even though Cbl-family E3 ligases normally function to trigger RTK downregulation. In combination with CD2AP, however, Cbl-3 promotes Ret degradation rapidly and almost completely blocks survival promotion by GDNF, suggesting that Cbl-3actsasaswitchthatistriggeredbyCD2APandoscillatesbetweeninhibitionandpromotionofRetdegradation.Consistentwiththe hypothesis, Cbl-3 silencing in neurons only inhibited Ret degradation and enhanced neuronal survival in combination with CD2AP silencing.CD2APandCbl-3,therefore,constituteacheckpointthatcontrolstheextentofRetdownregulationand,thereby,thesensitivity ofneuronstoGFLs." @default.
• W2182560250 created "2016-06-24" @default.
• W2182560250 creator A5069465056 @default.
• W2182560250 date "2008-01-01" @default.
• W2182560250 modified "2023-09-27" @default.
• W2182560250 title "CD2APandCbl-3/Cbl-cConstituteaCriticalCheckpointin theRegulationofRetSignalTransduction" @default.
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