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Istologia Corso di Laurea in Medicina e Chirurgia - A.A. 2002-03 Lezione 4 11 Marzo 2003 Ligand Inactive receptor monomers P P P P P P P P P P P P P P P P Active tyrosine kinase Signal transduction Kinase N-terminal lobe Receptor C-terminal tail Lys1110 (ATP/Mg++ bind.) Catalytic loop Asp1204 Tyr1234 Activation loop Tyr1235 Kinase C-terminal lobe Arg + _ SH2 P ----Tyr-----X------X-----hy---- SH2 PH SH2 SH3 P SH2 Kinase SH2 SH3 SH2 PTPase SH2 SH3 SH2 PH DNA bind. SH3 Src P PLC SH-PTP2 P SH2 GAP GAP P STAT Grb-2 SH3 SH2 SH3 PTB P PLC- Shc SH2 SH3 Pro SH2 SH2 PH PTB P P P P P P P P p85 PI3K IRS-1 Il cancro è una malattia dei tessuti GTP plasma membrane SoS RTK P GDP Ras Ras GTP Pi GAP/NF1 Ras GDP Grb2 Multiple signalling pathways SH2 SH3 PH PolyPro Point mutation in the GTPase domain plasma membrane RTK Ras GTP Pi GAP Ras GDP constitutive activation Multiple signalling pathways CANCER ! Tyrosine Kinase Receptor ? Ras GAP Rho GAP RalGEF Ral Rho ? Raf MEKK MEK SEK MAPK/ERK SAPK/JNK TCF, Ets Actin cytoskeleton rearrangements PDK PI-3K Akt Tiam1 S6K Rac PAK Jun, ATF2 TCF DNA transcription/Duplication Protein translation p38 Jun, ATF2 TCF Protection from apoptosis Ras Myc p21 p27 cyclinD cdk4 Rb P E2F DNA duplication Cell proliferation plasma membrane PIP2 P P Ras P PLC IP3 DAG P P Raf PH SH2 PIP3 P P P p85 PKC ? Ca++ PI3K PTEN P P PIP2 P P GDP Rac GTP Actin cytoskeleton PDK P Bad Akt P S6K PAK P SAPK Cell migration p38 Protein synthesis DNA duplication Cell survival Cell proliferation P plasma membrane P P MAPK P STAT P P nucleus P DNA Cell proliferation and/or differentiation P I segnali anti-proliferativi G0 Quiescent GZ Cell cycle Post-mitotic Differentiation TGF-, BMP, activin R2 R1 plasma membrane P Serine-threonine kinase Smad P 1,2 Smad 4 Smad 6 nucleus Smad P X 1,2 Smad 4 DNA Myc p15 cyc cdk Growth inhibition/differentiation TGF-, BMP, activin R2 R1 plasma membrane P Serine-threonine kinase Smad P 1,2 Smad 4 Smad 6 nucleus Smad P X 1,2 Smad 4 DNA Myc p15 cyc cdk Growth inhibition/differentiation Il cancro è una malattia dei tessuti
