BC212/week7/20031 BC212 Signal transduction & growth control Death receptor signaling.

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Presentation transcript:

BC212/week7/20031 BC212 Signal transduction & growth control Death receptor signaling

BC212/week7/20032 Lecture overview Death receptor signaling pathways: TNF/TNFR gene-families DISC signaling NF-kappaB signaling Discussion: FLIP: a switch between death & survival?

BC212/week7/20033 Lecture overview Death receptor signaling pathways: TNF/TNFR gene-families

BC212/week7/20034 TNF/TNFR families Ligands = typically membrane bound; at least 18 Receptors = one subunit; at least 28 Receptor-ligand promiscuity Decoy receptors Trimerization PLAD: pre-ligand assembly domain

BC212/week7/20035 TNF/TNFR families Ashkenazi Nat Rev Cancer 2:420, 2002

BC212/week7/20036 TNF/TNFR families

BC212/week7/20037 TNF/TNFR families Ashkenazi Nat Rev Cancer 2:420, 2002

BC212/week7/20038 TNF/TNFR families Goldstein Science 288:2388, 2000

BC212/week7/20039 TNF/TNFR families PLAD: pre-ligand assembly domain ALS (autoimmune lymphoproliferative syndrome): del (het) Siegel et al. Science 288:2354, 2000

BC212/week7/ Lecture overview

BC212/week7/ DISC signaling Cell death, survival and cancer Intrinsic versus extrinsic death pathways

BC212/week7/ DISC signaling Lost track of this reference

BC212/week7/ DISC signaling Death receptor ligands TRAIL (DR4, DR5) FasL (Fas) TNF (TNFR1) TWEAK (TWEAK-R)

BC212/week7/ DISC signaling

BC212/week7/ DISC signaling Death receptor pathway components: FADD DD & DED Caspase-8, -10 DED & caspase (protease) FLIP Dominant inhibitor caspase relative Caspase-3 (etc.) Extrinsic pathway (via Bid)

BC212/week7/ DISC signaling Ashkenazi Nat Rev Cancer 2:420, 2002

BC212/week7/ DISC signaling

BC212/week7/ DISC signaling

BC212/week7/ DISC signaling Identifying components Fas screen for cytotoxic antibodies antibody crosslinks/multimerizes Fas FasL cell line which killed Fas-expressing cells (only) FasFc blocked killing Used biotinylated FasFc to affinity purify FasL FADD two-hybrid screen for DD interactors

BC212/week7/ DISC signaling lpr and gld mice Lymphoproliferative phenotype Resembles SLE lpr: homozygous mutation in Fas DD gld: homozygous inactivating mutation in FasL Implicates Fas-FasL in immune cell apoptosis

BC212/week7/ DISC signaling Ashkenazi Nat Rev Cancer 2:420, 2002

BC212/week7/ DISC signaling Induced proximity model of caspase activation Parallels with kinase activation Evidence: i) artificial dimerization activates caspase ii) zymogen has low, but detectable, activity

BC212/week7/ Lecture overview

BC212/week7/ NFkappaB signaling Haefner Drug Discovery Today 7:

BC212/week7/ NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002

BC212/week7/ NFkappaB signaling Haefner Drug Discovery Today 7:

BC212/week7/ NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002

BC212/week7/ NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002

BC212/week7/ NFkappaB signaling Evidence linking NFkappaB to proliferation/cancer RelA: viral NFkappaB homolog incrd stability; decrd susceptibility to degradation Bcl3: chromosomal translocations in leukemia over-expression NFKB2: chromosomal translocation in leukemia/lymphoma deletes IkappaB part

BC212/week7/ NFkappaB signaling Evidence establishing mechanism of NFkappaB signaling 1.Isolation via enhancer affinity chromatography 2.PMA (cells) & DOC (extracts) induces EMSA activity 3.PMA stimulates transport to the nucleus 4.DOC-dissociable inhibitor (IkappaB) 5.NFkB-IkB complex disrupted, EMSA induced, by PKC 6.IkB degradation: proteosome inhs, Ub’n, etc.

BC212/week7/ NFkappaB signaling

BC212/week7/ NFkappaB signaling

BC212/week7/ Lecture overview

BC212/week7/ FLIP as a switch?