Signal Transduction: Pathways, Mechanisms and Diseases

Teachingagraduatecourseonsignaltransductioninthefallof2007wasvery enjoyable. Eachweek,mystudentsandIdiscussedarecentlypublishedresearch paperinsomeareaofsignaling,arguedabouttheappropriatenessofthemethod- ogyusedintheresearch,thedesignoftheexperiments,andwhethertheconc- sions drawn were supported bythe results presented. Finally, each student was askedtolistwhatwasgoodandwhatwasde?cientinthepaperandwhethershe/he wouldhaveacceptedorrejectedithadshe/herevieweditforpublication. Fora goodnumberofrecentpapers,aconsistentcomplaintofthestudentswasthatthe backgroundtotheresearchwasnotadequatelydescribed. Itcanofcoursebeargued that students should research the background. Either way, the need for a good sourceofbackgroundmaterialinordertoappreciatetheresearchpresentedina paperbecameapparenttomeandwastheinspirationfordevelopingthisbook. Thegoalinbringingthisbookwastoprovidestudentswithareviewofrecent developmentsinspeci?careasofcurrentinterestinsignaltransduction,suf?ciently indepthtomakerecentresearchpublicationsaccessible. However,giventhewide rangeofresearchtopicsbeinginvestigatedtodayinsignaling,achoicehadtobe madetofocusonaselectfew.Thischoicewasmadenotonlykeepingthecurrent research interest in mind, but also with the anticipation that these areas will continuetobeofinterestoverthenextseveralyears. Inchoosingpapersfordiscussioninmyclass,Ilookforhealth-relatednessofthe research,andthatisre?ectedinthelistofthebroadareascoveredinthisbook-G proteincoupledreceptors,growthfactors,nuclearreceptors,reactiveoxygenand nitrogenspecies,cellcycleandcancer;theemphasishasbeenonareasofsignaling researchwithimmediateclinicalsigni?cance. Ibelievethisbookwillservewellas supplementalreadingmaterialforundergraduateandgraduatestudentswithsimilar interest. Anotherareacoveredinthisbook,onenotoftenhighlightedinsignaltransd- tionbooks,isthatofsignalingplatforms,whichisemergingasasigni?cantareaof researchrelevanttocellularmetabolism,cellproliferation,differentiation,apop- sis,neurodegenerativediseases,andcancer. Theauthorscontributingtothisbook vii viii Preface areexpertsandactivecontributorstoresearchintheirspeci?careasofsignaling. I would like to thank them for their contributions and their suggestions in the developmentofthebook.IwouldliketoacknowledgethehelpofFrankTedeschi, astudentinmydepartment,whoassistedineditingthemanuscriptsandinprep- ingtheindex. IwouldalsoliketothankDr. SabineSchwarz,LifeSciencesEditorat SpringerVerlag,andDr. JuttaLindenbornwhohavebeenveryhelpfulatevery stageofproductionofthisbook. AriSitaramayya Contents PartI GProteinsandGProtein-Teachingagraduatecourseonsignaltransductioninthefallof2007wasvery enjoyable. Eachweek,mystudentsandIdiscussedarecentlypublishedresearch paperinsomeareaofsignaling,arguedabouttheappropriatenessofthemethod- ogyusedintheresearch,thedesignoftheexperiments,andwhethertheconc- sions drawn were supported bythe results presented. Finally, each student was askedtolistwhatwasgoodandwhatwasde?cientinthepaperandwhethershe/he wouldhaveacceptedorrejectedithadshe/herevieweditforpublication. Fora goodnumberofrecentpapers,aconsistentcomplaintofthestudentswasthatthe backgroundtotheresearchwasnotadequatelydescribed. Itcanofcoursebeargued that students should research the background. Either way, the need for a good sourceofbackgroundmaterialinordertoappreciatetheresearchpresentedina paperbecameapparenttomeandwastheinspirationfordevelopingthisbook.Thegoalinbringingthisbookwastoprovidestudentswithareviewofrecent developmentsinspeci?careasofcurrentinterestinsignaltransduction,suf?ciently indepthtomakerecentresearchpublicationsaccessible. However,giventhewide rangeofresearchtopicsbeinginvestigatedtodayinsignaling,achoicehadtobe madetofocusonaselectfew. Thischoicewasmadenotonlykeepingthecurrent research interest in mind, but also with the anticipation that these areas will continuetobeofinterestoverthenextseveralyears. Inchoosingpapersfordiscussioninmyclass,Ilookforhealth-relatednessofthe research,andthatisre?ectedinthelistofthebroadareascoveredinthisbook-G proteincoupledreceptors,growthfactors,nuclearreceptors,reactiveoxygenand nitrogenspecies,cellcycleandcancer;theemphasishasbeenonareasofsignaling researchwithimmediateclinicalsigni?cance. Ibelievethisbookwillservewellas supplementalreadingmaterialforundergraduateandgraduatestudentswithsimilar interest. Anotherareacoveredinthisbook,onenotoftenhighlightedinsignaltransd- tionbooks,isthatofsignalingplatforms,whichisemergingasasigni?cantareaof researchrelevanttocellularmetabolism,cellproliferation,differentiation,apop- sis,neurodegenerativediseases,andcancer.Theauthorscontributingtothisbook vii viii Preface areexpertsandactivecontributorstoresearchintheirspeci?careasofsignaling. I would like to thank them for their contributions and their suggestions in the developmentofthebook. IwouldliketoacknowledgethehelpofFrankTedeschi, astudentinmydepartment,whoassistedineditingthemanuscriptsandinprep- ingtheindex. IwouldalsoliketothankDr. SabineSchwarz,LifeSciencesEditorat SpringerVerlag,andDr. JuttaLindenbornwhohavebeenveryhelpfulatevery stageofproductionofthisbook. AriSitaramayya Contents PartI GProteinsandGProtein-CoupledReceptors 1 TraditionalGPCRPharmacologyandBeyond...3 AnnetteGilchristandMariaR. Mazzoni 2 RegulationofIntraneuronalTraf?ckingofG-Protein-Coupled ReceptorsbyNeurotransmittersInVivo ...25 Ve'roniqueBernard 3 SmallGTPasesandTheirRoleinRegulatingGProtein-Coupled ReceptorSignalTransduction ...43 FabiolaM. RibeiroandStephenS. G. Ferguson 4 RegulationofGProteinReceptorCoupling,MoodDisorders andMechanismofActionofAntidepressants ...63 MoranGolan,GabrielSchreiber,andSo?aAvissar 5 DysregulationofGProtein-CoupledReceptorSignaling inCancer ...83 JoAnnTrejo PartII GrowthFactors 6 InsulinSignalinginNormalandDiabeticConditions ...101 PatriceEFort,HisanoriImai,RajuRajala,andThomasW. Gardner 7 EpidermalGrowthFactor(EGF)ReceptorSignaling andCancer ...119 ElizabethS. HensonandSpencerB. Gibson ix x Contents 8 LeptinSignalingPathway...143 HiroyukiShimizu 9 SignalinginNormalandPathologicalAngiogenesis...159 MichaelR. MancusoandCalvinJ. Kuo PartIII SignalingPlatforms 10 SpatialandTemporalControlofCellSignaling byA-KinaseAnchoringProteins...183 F. DonelsonSmith,LoreneK. Langeberg,andJohnD. Scott 11 Mitochondria,aPlatformforDiverseSignalingPathways ...199 AstridC. SchaussandHeidiM. McBridee 12 Mitogen-ActivatedProteinKinases andTheirScaffoldingProteins ...219 DannyN. DhanasekaranandE. PremkumarReddy 2p 13 MolecularandFunctionalDeterminantsofCa SignalingMicrodomains ...237 InduS. Ambudkar,HweiL. Ong,andBrijB. Singh PartIV NuclearReceptors/Transcription 14 EukaryoticGeneTranscription ...257 JenniferH. GromekandArikDvir 15 EstrogenSignalingMechanisms...273 DapengZhangandVanceL. Trudeau 16 SignalTransductionPathwaysInvolved inGlucocorticoidActions ...289 PeterJ. Barnes PartV ReactiveSignalingMolecules 17 CellularSignalingbyReactiveOxygenSpecies:Biochemical BasisandPhysiologicalScope ...313 ' MichelB.Toledano,SimonFourquet,andBeno?tD'G proteincoupledreceptors,growthfactors,nuclearreceptors,reactiveoxygenand nitrogenspecies,cellcycleandcancer;theemphasishasbeenonareasofsignaling researchwithimmediateclinicalsigni?cance. Ibelievethisbookwillservewellas supplementalreadingmaterialforundergraduateandgraduatestudentswithsimilar interest. Anotherareacoveredinthisbook,onenotoftenhighlightedinsignaltransd- tionbooks,isthatofsignalingplatforms,whichisemergingasasigni?cantareaof researchrelevanttocellularmetabolism,cellproliferation,differentiation,apop- sis,neurodegenerativediseases,andcancer. Theauthorscontributingtothisbook vii viii Preface areexpertsandactivecontributorstoresearchintheirspeci?careasofsignaling. I would like to thank them for their contributions and their suggestions in the developmentofthebook. IwouldliketoacknowledgethehelpofFrankTedeschi, astudentinmydepartment,whoassistedineditingthemanuscriptsandinprep- ingtheindex. IwouldalsoliketothankDr. SabineSchwarz,LifeSciencesEditorat SpringerVerlag,andDr. JuttaLindenbornwhohavebeenveryhelpfulatevery stageofproductionofthisbook.AriSitaramayya Contents PartI GProteinsandGProtein-CoupledReceptors 1 TraditionalGPCRPharmacologyandBeyond...3 AnnetteGilchristandMariaR. Mazzoni 2 RegulationofIntraneuronalTraf?ckingofG-Protein-Coupled ReceptorsbyNeurotransmittersInVivo ...25 Ve'roniqueBernard 3 SmallGTPasesandTheirRoleinRegulatingGProtein-Coupled ReceptorSignalTransduction ...43 FabiolaM. RibeiroandStephenS. G. Ferguson 4 RegulationofGProteinReceptorCoupling,MoodDisorders andMechanismofActionofAntidepressants ...63 MoranGolan,GabrielSchreiber,andSo?aAvissar 5 DysregulationofGProtein-CoupledReceptorSignaling inCancer ...83 JoAnnTrejo PartII GrowthFactors 6 InsulinSignalinginNormalandDiabeticConditions ...101 PatriceEFort,HisanoriImai,RajuRajala,andThomasW. Gardner 7 EpidermalGrowthFactor(EGF)ReceptorSignaling andCancer ...119 ElizabethS. HensonandSpencerB. Gibson ix x Contents 8 LeptinSignalingPathway...143 HiroyukiShimizu 9 SignalinginNormalandPathologicalAngiogenesis...159 MichaelR. MancusoandCalvinJ. Kuo PartIII SignalingPlatforms 10 SpatialandTemporalControlofCellSignaling byA-KinaseAnchoringProteins...183 F. DonelsonSmith,LoreneK. Langeberg,andJohnD.Scott 11 Mitochondria,aPlatformforDiverseSignalingPathways ...199 AstridC. SchaussandHeidiM. McBridee 12 Mitogen-ActivatedProteinKinases andTheirScaffoldingProteins ...219 DannyN. DhanasekaranandE. PremkumarReddy 2p 13 MolecularandFunctionalDeterminantsofCa SignalingMicrodomains ...237 InduS. Ambudkar,HweiL. Ong,andBrijB. Singh PartIV NuclearReceptors/Transcription 14 EukaryoticGeneTranscription ...257 JenniferH. GromekandArikDvir 15 EstrogenSignalingMechanisms...273 DapengZhangandVanceL. Trudeau 16 SignalTransductionPathwaysInvolved inGlucocorticoidActions ...289 PeterJ. Barnes PartV ReactiveSignalingMolecules 17 CellularSignalingbyReactiveOxygenSpecies:Biochemical BasisandPhysiologicalScope ...313 ' MichelB. Toledano,SimonFourquet,andBeno?tD'Autreaux 18 SolubleGuanylylCyclase:TheNitricOxideReceptor...337 DorisKoeslingandAriSitaramayya Contents xi PartVI CellCycle,CellDeathandCancer 19 DistinctRolesofthePocketProteinsintheControl ofCellCycle...353 ParaskeviVogiatziandPierPaoloClaudio 20 Activationofthep53TumorSuppressoranditsMultipleRoles inCellCycleandApoptosis...375 LucianaE. GionoandJamesJ. Manfredi 21 AgingandCancer:CaretakersandGatekeepers ...397 DianavanHeemst 22 SignalTransductioninEmbryonicStemCells andtheRiseofiPSCells ...