DOC PREVIEW
MIT 7 61 - Generic Signal Transduction Pathways

This preview shows page 1-2-20-21 out of 21 pages.

Save
View full document
View full document
Premium Document
Do you want full access? Go Premium and unlock all 21 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 21 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 21 pages.
Access to all documents
Download any document
Ad free experience
View full document
Premium Document
Do you want full access? Go Premium and unlock all 21 pages.
Access to all documents
Download any document
Ad free experience
Premium Document
Do you want full access? Go Premium and unlock all 21 pages.
Access to all documents
Download any document
Ad free experience

Unformatted text preview:

1Generic Signal Transduction PathwaysProliferationSurvivalDifferentiationApoptosisCytoskeletonLIGANDSRECEPTORSADAPTORSEFFECTORSOUTPUTSDownward, J. 2001Nature N&VLnRnGnCHANNELSAC 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 Kinases 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 interactionsAsymmetricAlso Epo/EpoRKosiakoff, De Vosand Wells6VEGF/VEGFR1 dimeric ligand2 receptorsR-R interactionsSymmetricalso PDGF, NGF, TGF/BMPWiesman et al, Cell 91:695-704 1997EGF/EGFR2 monomeric ligands2 receptorsR-R interactionsSymmetric7FGF/FGFR2 monomeric ligands2 receptors2 heparin chainsR-R interactionsOverall symmetric but L-R binding istwo-site, asymmetricSchlessinger et al, Mol. Cell 6: 743-750 2000Mohammadi et al, Curr Opin Struc Biol. 15: 506-516, 2005Receptor Autoinhibition• EGFR extracellular domain undergoes conf. change on EGF binding• BUT EGFR extracellular domain does not dimerize on EGF binding• Intact EGFR DOES dimerize on EGF binding• MODEL - ECD conformation blocks dimerization (autoinhibition)and that is relieved by ligand• sEGFR is mostly monomeric and low affinity (400-550 nM)• there is a small population (~5%) with high affinity (2-20 nM)• deletion of domain IV converts it to high affinity (13-21 nM)8Autoinhibition of EGFRsIVCho and LeahyScience (2002)EGFEGFEGFAutoinhibition of FGFRsFGFRFGFFGFD3D2D3D2D1D1D19PDGF-ReceptorRecruitment of signal transducersto tyrosine phosphatesProtein Modules Recruiting Signaling Proteins to Receptors and to the Membrane10Insulin Receptor Substrate (IRS)etcAn alternative way to recruitsignal transducers-Y-PP-Y--Y-PY-PP-YIRS11Different Mechanisms for Activating Signaling Proteins Recruitmentplus Activation& PhosphorylationRecruitment with ConformationalChange -> ActivationRecruitment plus Phosphorylation -> ActivationReceptor -> MAPKinase pathwayMAPKMAPKKMAPKKKMAPKK and MAPKactivations involveBOTH Y and S/Tphosphorylations12Evolutionary Conservation ofMAPKinase PathwaysMAPKMAPKKMAPKKKEffectorsMAP Kinase Pathways/CascadesWhy cascades? How does the cell keep modules separate?13switchesFerrell, TIBS 21: 460-466 (1996)Cascade as a switch mechanismMos -> ->ErkIs there amplification? Model Results0 0.5 1 1.5 2 2.5 3 3.5 4 4.5 500.10.20.30.40.50.60.70.80.91Fig. 1: Replica of Fig. 2A - Predicted responses on a linear plotInput stimulus (E1tot in multiples of the EC50)Predicted Steady-State Kinase ActivityMAPKKKMAPKKMAPKMAPKKKMAPK10-610-510-410-310-210-100.10.20.30.40.50.60.70.80.91Fig. 2: Replica of Fig. 2B - Predicted responses on a semi-logarithmic plotInput stimulus (E1tot)Predicted Steady-State Kinase ActivityMAPKKKMAPKKMAPKMAPKKKMAPKnH = 1.0nH = 4.9Huang C.F. & Ferrell J.E. (1996) PNAS 93, 10078-8314Experimental ValidationHuang C.F. & Ferrell J.E. (1996) PNAS 93, 10078-83Scaffolds for MAPK modulesSte11pSte7pFus3pMAPKKK MAPKK MAPKSte5pMLKMKK7JNKJIP1MLKMKK3p38JIP2kinesin15More 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)RTK-P RTK PhosphataseLigandSignalingKinase*KinaseRLigandSignalingPhosphataseReceptor-intrinsickinasesReceptor-associatedkinases16ITAM - YxxLx6-8YxxLSrc family kinaseITAM-binding(2xSH2) kinaseMHC/peptideCD3 complexTCRT Cell Receptor SignalingP PCytokine ReceptorsShared signaling subunits - different ligand-binding subunits17JAK/StatIRS etcCytokine ReceptorsSignaling PathwaysTGF! Receptor Family - S/T KinasesIIIIII18TGF! Receptor Family - SMAD SignalingTGF! Receptor Family -Regulators and Feedback Loops19Protein Tyrosine PhosphatasesProtein Tyrosine Phosphatases20Structure of PTPase domainD1 from receptor-likeProtein phosphatase-#Bilwes et al. Nature 382:555-559(1996)wedgeactive siteT Cell Receptor SignalingSrc family kinaseITAM-binding(2xSH2) kinaseMHC/peptideCD3 complexTCRCD4521Negative Feedback


View Full Document

MIT 7 61 - Generic Signal Transduction Pathways

Documents in this Course
Load more
Download Generic Signal Transduction Pathways
Our administrator received your request to download this document. We will send you the file to your email shortly.
Loading Unlocking...
Login

Join to view Generic Signal Transduction Pathways and access 3M+ class-specific study document.

or
We will never post anything without your permission.
Don't have an account?
Sign Up

Join to view Generic Signal Transduction Pathways 2 2 and access 3M+ class-specific study document.

or

By creating an account you agree to our Privacy Policy and Terms Of Use

Already a member?