Role of Ubiquitination in IGF-1 Receptor Signaling and Degradation 英文参考文献.docVIP

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Role of Ubiquitination in IGF-1 Receptor Signaling and Degradation 英文参考文献.doc

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Role of Ubiquitination in IGF-1 Receptor Signaling and Degradation 英文参考文献

RoleofUbiquitinationinIGF-1ReceptorSignalingand Degradation BitaSehat,SandraAndersson,RaduVasilcanu,LeonardGirnita,OlleLarsson* DepartmentofOncologyandPathology,CancerCentreKarolinska(CCK),KarolinskaInstitutetandKarolinskaUniversityHospital-Solna,Stockholm, Sweden Background.Theinsulin-likegrowthfactor1receptor(IGF-1R)playsnumerouscrucialrolesincancerbiology.Themajorityof knowledge on IGF-1R signaling is concerned with its role in the activation of the canonical phosphatidyl inositol-3 kinase (PI3K)/AktandMAPK/ERKpathways.However,theroleofIGF-1RubiquitinationinmodulatingIGF-1Rfunctionisanareaof currentresearch.InlightofthiswesoughttodeterminetherelationshipbetweenIGF-1Rphosphorylation,ubiquitination,and modulation of growth signals. Methodology. Wild type and mutant constructs of IGF-1R were transfected into IGF-1R null fibroblasts. IGF-1Rautophosphorylation andubiquitination weredeterminedbyimmunoprecipitationandwesternblotting. IGF-1R degradation and stability was determined by cyclohexamide-chase assay in combination with lysosome and proteasomeinhibitors.PrincipalFindings.IGF-1Rautophosphorylationwasfoundtobeanabsoluterequirementforreceptor ubiquitination.DeletionofC-terminaldomainhadminimaleffectonIGF-1inducedreceptorautophosphorylation,however, ubiquitinationandERKactivationwerecompletelyabolished.CellsexpressingkinaseimpairedIGF-1R,exhibitedbothreceptor ubiquitination and ERK phosphorylation, however failed to activate Akt. While IGF-1R mutants with impaired PI3K/Akt signaling were degraded mainly by the proteasomes, the C-terminal truncated one was exclusively degraded through the lysosomal pathway. Conclusions. Our data suggest important roles of ubiquitination in mediating IGF-1R signaling and degradation. Ubiquitination of IGF-1R requires receptor tyrosine kinase activity, but is not involved in Akt activation. In additionweshowthattheC-terminaldomainofIGF-1RisanecessaryrequisiteforubiquitinationandERKphosphorylationas wellasforproteasomaldegradationof