肿瘤问题.PPT

CANCER: Stroma: ANGIOGENESIS ANGIOGENESIS / CANCER INVASION ANGIOGENESIS / CANCER INVASION ANGIOGENESIS / CANCER INVASION VEGF Rs ANGIOGENESIS / CANCER INVASION ANGIOGENESIS / CANCER INVASION ANGIOGENESIS / CANCER INVASION Enigmas APOPTOSIS Mitochondrion / Cytoplasm Mitochondria-death Signal Integrators Enigmas in Apoptosis HOT SPOTS OF SIGNALING Human RPTK Human Cytoplasmic PTK PI(3)K / Akt mTOR / p7056k (rapamycin target) Akt ( PKB ) Substrate of Akt-1 Substrate of Akt: 13: RXRXXS/T motif  (this motif:also for MAPKAPK-1 p7056K) PDK1/Akt activation: PTEN mTOR ( Mammalian Target of Rapamycin ) Ribosomal S6 Kinase S6K1, S6K2 Wnt Pathway Wnt Pathway Hedgehog Pothway Activation of hh Pathway Akt: v- Akt homolog PKB a, b, g isoforms N’ – PH domain Central kinase domain – activation loop: Thr. 308 C’ – Regulatory site: Ser 473 PDK- 1 (3’-phospho-inositide dependent Kinase 1) : Thr 308 Akt kinase C’ – PH domain 10 fold binding affinity to lipid membrane (constitutively binding) PDK-2: Ser 473 Akt p21WAF-1 ( ? , via FKHR ) PDE-3B (Phosphodiesterase –3B) ( ? ) GSK-3 (Glycogen synthase K) ( ? ) (Cyclin D ? ) ( b-catenin ? ) CREB (cAMP Response element) ( ? ) BRCA 1 ( ? ) Bad ( ? ) eNOS ( ? ) FKHR (Forkhead TA) ( ? ) Regulator of cell growth Anti-apoptosis Class 2 Class 1 Two major class RPTK activation ? P1(3)k ? Ptd Ins (3,4,5) P3 Ptd Ins(3,4)P2 Interact with AKT Akt / PDK1 ? Akt translocatin to membrane ? Thr 308 (loop) ? Ser 473 (Reg. Site) (PDK2 ?) Akt P P translocate to nuclei AKT P P PDK1 also－ ? PKC isoforms, ser