PDP-1 Links the TGF-β and IIS Pathways to Regulate Longevity, Development, and Metabolism 英文参考文献.docVIP

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PDP-1 Links the TGF-β and IIS Pathways to Regulate Longevity, Development, and Metabolism 英文参考文献.doc

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PDP-1 Links the TGF-β and IIS Pathways to Regulate Longevity, Development, and Metabolism 英文参考文献

PDP-1LinkstheTGF-bandIISPathwaystoRegulate Longevity,Development,andMetabolism SriDeviNarasimhan1,KelvinYen1,AnkitaBansal1,Eun-SooKwon1,SrivatsanPadmanabhan1,HeidiA. Tissenbaum1,2 * 1PrograminGeneFunctionandExpression,UniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica, 2PrograminMolecular Medicine,UniversityofMassachusettsMedicalSchool,Worcester,Massachusetts,UnitedStatesofAmerica Abstract The insulin/IGF-1 signaling (IIS) pathway is a conserved regulator of longevity, development, and metabolism. In Caenorhabditis elegans IIS involves activation of DAF-2 (insulin/IGF-1 receptor tyrosine kinase), AGE-1 (PI 3-kinase), and additional downstream serine/threonine kinases that ultimately phosphorylate and negatively regulate the single FOXO transcription factor homolog DAF-16.Phosphatases help to maintain cellular signaling homeostasis by counterbalancing kinaseactivity.However,fewphosphataseshavebeenidentifiedthatnegativelyregulatetheIISpathway.Hereweidentify andcharacterizepdp-1asanovelnegativemodulatoroftheIISpathway.WeshowthatPDP-1regulatesmultipleoutputsof IIS such as longevity, fat storage, and dauer diapause. In addition, PDP-1 promotes DAF-16 nuclear localization and transcriptionalactivity.Interestingly,geneticepistasisanalysesplacePDP-1intheDAF-7/TGF-bsignalingpathway,atthe leveloftheR-SMADproteinsDAF-14andDAF-8.FurtherinvestigationintohowacomponentofTGF-bsignalingaffects multipleoutputsofIIS/DAF-16,revealedextensivecrosstalkbetweenthesetwowell-conservedsignalingpathways.Wefind thatPDP-1modulatestheexpressionofseveralinsulingenesthatarelikelytofeedintotheIISpathwaytoregulateDAF-16 activity. Importantly, dysregulation of IIS and TGF-b signaling has been implicated in diseases such as Type 2 Diabetes, obesity,andcancer.Ourresultsmayprovideanewperspectiveinunderstandingoftheregulationofthesepathwaysunder normalconditionsandinthecontextofdisease. Citation:NarasimhanSD,YenK,BansalA,KwonE-S,PadmanabhanS,etal.(2011)PDP-1Lin