1Generic Signal Transduction PathwaysProliferationSurvivalDifferentiationApoptosisCytoskeletonLIGANDSRECEPTORSADAPTORSEFFECTORSOUTPUTSLnRnGnYCHANNELSAC cAMPcAKinasePDE cGMPcGKinaseCHANNELSPLAPLCArachidonicacidProstaglandinsEicosanoidsPIP2IP3Ca++CaMKinaseDAGKinase CPI derivativesKinase B/AktPI3K2RECEPTORSTRANSDUCERS EFFECTORS (proximal)“SECOND MESSENGERS”SERPENTINE (7TM)HETEROTRIMERICG PROTEINSADENYLATE CYCLASEPHOSPHODI- ESTERASEPHOSPHO-LIPASE C!PI3 KINASECHANNELScAMPcGMPDERIVATIVESDERIVATIVES Ca++PHOSPHATIDYLINOSITOLPHOSPHATESIONS+DIACYLGLYCEROLIP3GsGiGtGoGq !"Gt!"various incl.!"ADENYLATE CYCLASEPHOSPHO-DIESTERASEGs GiGtcAMPcGMPNote:There are alsoGuanylate KinaseReceptors3SECOND MESSENGER EFFECTORScAMPcGMPCa++DAGPKC Protein Kinase CPKA Protein Kinase ACalmodulin (CaM)CaM KinasesOther Ca++-activated kinases eg MLCKOther effectors - cAMP phosphodiesterase- Calcineurin, a Ca++-activated phosphatase- cytoskeleton Some but not all Ca++- dependentActivated by phorbol estersChannels/PumpscGMP-dependent kinasesPM-NUCLEUSSee alsoBrivanlou & DarnellScience 295:813-818(2002)4RTK-P RTK PhosphataseLigandSignalingGGTPGGDPLigandSignalingGEFsGAPsRGSsGDIsReceptor Protein Tyrosine KinasesIgFn3HGF/SFNeurotrophinsEphrins Gas65Dimerization Trans-phosphorylationRecruitmentActivationHGH/HGHR1 monomeric ligand2 receptorsR-R interactionsAlso Epo/EpoRKosiakoff, De Vosand Wells6VEGF/VEGFR1 dimeric ligand2 receptorsR-R interactionsalso PDGF, NGF, TGF/BMPWiesman et al, Cell 91:695-704 1997EGF/EGFR2 monomeric ligands2 receptorsR-R interactions7FGF/FGFR2 monomeric ligands2 receptors1 heparin chainR-R interactionsPDGF-ReceptorRecruitment of signal transducersto tyrosine phosphates8Protein Modules Recruiting Signaling Proteins to Receptors and to the Membrane9Insulin Receptor Substrate (IRS)etcAn alternative way to recruitsignal transducers-Y-PP-Y--Y-PY-PP-YIRSDifferent Mechanisms for Activating Signaling Proteins Recruitmentplus Activation& PhosphorylationRecruitment with ConformationalChange -> ActivationRecruitment plus Phosphorylation -> Activation10Receptor -> MAPKinase pathwayMAPKMAPKKMAPKKKEvolutionary Conservation ofMAPKinase Pathways11MAPKMAPKKMAPKKKEffectorsMAP Kinase Pathways/CascadesWhy cascades? How does the cell keep modules separate?switchesFerrell, TIBS 21: 460-466 (1996)Cascade as a switch mechanismMos -> ->ErkIs there amplification?12Scaffolds for MAPK modulesSte11pSte7pFus3pMAPKKK MAPKK MAPKSte5pMLKMKK7JNKJIP1MLKMKK3p38JIP2kinesinMore Scaffolds for MAPK modulesMEK1ERK1MAPKKK MAPKK MAPKMP1late endosomesp14FocalcontactsSH2-SH3-SH3CrkIIp130CaspaxillinC3GSOSDOCK180(via PPxLPxK)GEFsalso in JNKMutation blocks JNK activation by EGF/rac but not by UV!-arrestinsGPCR/arr/raf/erkcomplexes onendocytosisMorrison & DavisARCDB 19:91-118(2003)13RTK-P RTK PhosphataseLigandSignalingKinase*KinaseRLigandSignalingPhosphataseReceptor-intrinsickinasesReceptor-associatedkinasesITAM - YxxLx6-8YxxLSrc family kinaseITAM-binding(2xSH2) kinaseMHC/peptideCD3 complexTCRT Cell Receptor SignalingP P14Cytokine ReceptorsShared signaling subunits - different ligand-binding subunitsJAK/StatIRS etcCytokine ReceptorsSignaling Pathways15TGF! Receptor Family - S/T KinasesIIIIIITGF! Receptor Family - SMAD Signaling16TGF! Receptor Family -Regulators and Feedback LoopsProtein Tyrosine Phosphatases17Protein Tyrosine PhosphatasesStructure of PTPase domainD1 from receptor-likeProtein phosphatase-#Bilwes et al. Nature 382:555-559(1996)wedgeactive site18T Cell Receptor SignalingSrc family kinaseITAM-binding(2xSH2) kinaseMHC/peptideCD3 complexTCRCD45Negative Feedback
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