1 / 34

BC212 Signal transduction & growth control Death receptor signaling

BC212 Signal transduction & growth control Death receptor signaling. Lecture overview. Death receptor signaling pathways: TNF/TNFR gene-families DISC signaling NF-kappaB signaling ------------------------------------------ Discussion: FLIP: a switch between death & survival?.

mac
Download Presentation

BC212 Signal transduction & growth control Death receptor signaling

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. BC212Signal transduction & growth controlDeath receptor signaling BC212/week7/2003

  2. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling • NF-kappaB signaling • ------------------------------------------ • Discussion: FLIP: a switch between death & survival? BC212/week7/2003

  3. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families BC212/week7/2003

  4. 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/week7/2003

  5. TNF/TNFR families Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  6. 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/week7/2003

  7. TNF/TNFR families Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  8. TNF/TNFR families Goldstein Science 288:2388, 2000 BC212/week7/2003

  9. TNF/TNFR families PLAD: pre-ligand assembly domain ALS (autoimmune lymphoproliferative syndrome): del 52-96 (het) Siegel et al. Science 288:2354, 2000 BC212/week7/2003

  10. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling BC212/week7/2003

  11. DISC signaling • Cell death, survival and cancer • Intrinsic versus extrinsic death pathways BC212/week7/2003

  12. DISC signaling Lost track of this reference BC212/week7/2003

  13. DISC signaling • Death receptor ligands • TRAIL (DR4, DR5) • FasL (Fas) • TNF (TNFR1) • TWEAK (TWEAK-R) BC212/week7/2003

  14. DISC signaling BC212/week7/2003

  15. 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/week7/2003

  16. DISC signaling Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  17. DISC signaling BC212/week7/2003

  18. DISC signaling BC212/week7/2003

  19. 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/week7/2003

  20. 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/week7/2003

  21. DISC signaling Ashkenazi Nat Rev Cancer 2:420, 2002 BC212/week7/2003

  22. 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/week7/2003

  23. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling • NF-kappaB signaling BC212/week7/2003

  24. NFkappaB signaling Haefner Drug Discovery Today 7:653 2002 BC212/week7/2003

  25. NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002 BC212/week7/2003

  26. NFkappaB signaling Haefner Drug Discovery Today 7:653 2002 BC212/week7/2003

  27. NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002 BC212/week7/2003

  28. NFkappaB signaling Karin, et al Nat Rev Cancer 2:301, 2002 BC212/week7/2003

  29. 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/week7/2003

  30. NFkappaB signaling • Evidence establishing mechanism of NFkappaB signaling • Isolation via enhancer affinity chromatography • PMA (cells) & DOC (extracts) induces EMSA activity • PMA stimulates transport to the nucleus • DOC-dissociable inhibitor (IkappaB) • NFkB-IkB complex disrupted, EMSA induced, by PKC • IkB degradation: proteosome inhs, Ub’n, etc. BC212/week7/2003

  31. NFkappaB signaling BC212/week7/2003

  32. NFkappaB signaling BC212/week7/2003

  33. Lecture overview • Death receptor signaling pathways: • TNF/TNFR gene-families • DISC signaling • NF-kappaB signaling • ------------------------------------------ • Discussion: FLIP: a switch between death & survival? BC212/week7/2003

  34. FLIP as a switch? BC212/week7/2003

More Related