750 likes | 907 Views
Introduction to the Basics of Signal Transduction. Mauricio Lema Medellín, Colombia. … Porque algunos en la audiencia no hablan español. Y ellos también fueron invitados. Signal Transduction. Introduction / Definition Components of ST Selected pathways Some newer drug targets Cross-Talk
E N D
Introduction to the Basics of Signal Transduction Mauricio Lema Medellín, Colombia
… Porque algunos en la audiencia no hablan español. Y ellos también fueron invitados.
Signal Transduction • Introduction / Definition • Components of ST • Selected pathways • Some newer drug targets • Cross-Talk • Concluding remarks
Growth factors Nutrients & O2 Hormones Cell-Cell inter.
Signal Transduction Signal transduction describes the process through which extracellular signaling molecules bind specific receptors on target cells, which consequently activate selected intracellular biochemical pathways
Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors
Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors
Kinases Post-translational modifications are key to signal transduction • Phospholylation of Ser / Thr / Tyr may TURN ON / OFF a specific protein • The balance of P / de-P will establish a response
Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors
Signal Transduction - Components • Transcription factors • Kinases / Phosphorylases • Adaptors • Scafolds • Receptors
Signal Transduction Pathways • “Growth Factor” pathways • Rb • c-myc • TGFB • Hypoxia pathway • mTOR • IGR • MET • VEGF • EGFR
PI3K inhibitors RAF inhibitors Temsirolimus / Everolimus
PI3K inhibitors Raf Inhibitors
Shc Grb2 PI3-K Sos-1 Ras AKT Raf MEKK-1 MEK mTOR MKK-7 ERK JNK Angiogenesis Metastasis Apoptosis Resistance Proliferation Signaling EGFR
VEGF ANGIOGENESIS PLC PLC PI3-K PI3-K FAK FAK Ras Ras P P P P PKC PKC IP3 IP3 AKT AKT Paxillin Paxillin MAPK MAPK Migration Migration Survival Survival Proliferation Proliferation ANGIOGENESIS VEGF Binding & Activation of VEGFR Endothelial-Cell activation
Let’s put it simple… Signal – Receptor interaction
Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC
Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC Some “further” P is exchanged ERK mTOR Rb
Let’s put it simple… Signal – Receptor interaction Some P is exchanged Ras PI3k PKC Some “further” P is exchanged ERK mTOR Rb EFFECTOR TF – DNA interaction
Signal Transduction • Introduction / Definition • Components of ST • Selected pathways • Some newer drug targets • Cross-Talk • Concluding remarks
Cyclin Dependent Kinases Inhibitor • SCH 727965 (J. Nemunaitis, P.ASCO 2009, Abstract 3535) • 0/43 Responses
Raf Kinase Inhibitor • XL-281 (GK Schwartz, P.ASCO 2009, Abstract 3513) • 1/30 PR • 12/30 SD HSP • Alvespimycin (SC Pacvev, P. ASCO 2009, 3534) • 2/25 PR • OGX-427 (SJ Hotter, P. ASCO 2009, 3506) • 5/34 SD
Akt inhibitor • MK-2206 (AW Tolcher, P.ASCO 2009, Abstract 3503) • 6/19 SD
PI3K inhibitors • XL-147 (G. Shapiro, P.ASCO 2009, Abstract 3500) • 6/39 SD • GDC-0941 (AJ Wagner, P.ASCO 2009, Abstract 3501) • 3/19 SD • XL-765 (P. LoRusso, P.ASCO 2009, Abstract 3502) • 5/34 SD • Enzastaurin (MA Carducci, P.ASCO 2009, Abstract 3517) • 9/43 PR (Con Bevacizumab)
IGF1R/Aurora/SRC inhibitor • XL 228 (DC. Smith, P.ASCO 2009, Abstract 3512) • 1/30 PR • 9/30 SD