![Principes om [Ca2+] laag te houden in de cel (10-3 vs 10-7) Plasma membraan: Na+-driven Ca2+-antiport Ca2+-ATPase Interne membranen ER: Ca2+-ATPase Calcium bindende eiwitten Mitochondrien: actieve import](data:image/gif;base64,R0lGODlhAQABAIAAAAAAAP///yH5BAEAAAAALAAAAAABAAEAAAIBRAA7)
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- 2. Principes om [Ca2+] laag te houden in de cel (10-3 vs 10-7) Plasma membraan: Na+-driven Ca2+-antiport Ca2+-ATPase Interne membranen ER: Ca2+-ATPase Calcium bindende eiwitten Mitochondrien: actieve import
- 3. Calcium wave in fertilized egg
- 4. Calmoduline: een veel gebruikt calcium "receptor"
- 5. "Dual regulation" van CaCM (calmodulin) kinase
- 6. Dual regulation of "multisubunit" phosphorylase kinase Complex bevat eigenlijk vier subunits van elk
- 8. General structure Receptor tyrosine kinase Figure 5.9a The Biology of Cancer (© Garland Science 2007)
- 9. Many different types of RTKs: different ligand binding sites Figure 5.10 The Biology of Cancer (© Garland Science 2007)
- 10. Many different types of RTKs: different but overlapping intracellular docking domains Figure 6.9 The Biology of Cancer (© Garland Science 2007)
- 11. 1. Ligand binding 2. Dimerisatie 3. Activatie kinase 4. Kruisfosforylering General principle of activation Dimerisation + activation
- 12. Sometimes the kinase is associated
- 13. Tyrosine gefosforyleerde receptor fungeert als "docking site" voor signalerings enzymen
- 14. Signaleringsroutes: vorming van eiwit complexen via specifieke eiwit-domeinen
- 15. Adaptor eiwitten bevatten vaak meerdere “herkenningsdomeinen”
- 16. Receptor tyrosine kinases maken vaak gebruik van specifieke membraan-gebonden "docking proteins"
- 17. One of the effects of RTK activation: activation of the G-binding protein Ras 1: RTK bindt complex van Grb2 en Sos 2: Sos is guanine nucleotide exchange factor voor Ras 3: GDP wordt uitgewisseld voor GTP Grb2 Sos
- 18. Ras, a molecular switch GDP GEF GTP Ras Ras Effector GAP Mutated in tumors vvvvvv GEF: guanine nucleotide exchange factor GAP: GTPase activating protein
- 19. Mechanism of Ras activation by guanine nucleotide exchange factor
- 20. Mechanism of Ras inactivation by GTPase activating protein Mechanisme van GAP geinduceerde hydrolyse
- 21. Visualisation of Ras activation by FRET FRET (fluorescent resonance energy transfer) Mochizuli et al., Nature , 411 (2001) 1066
- 22. Ras activates Raf-MEK-ERK pathway (a MAP kinase cascade Raf MEK: MAP-ERK kinase MEK ERK: extracellular signal-regulated kinase Also called: MAP kinase ERK
- 23. Many stimuli can activate Ras by different mechanisms
- 24. Cycl D1 Ets ERK PLCe Endocytosis Cell cycle control MEK Rab5 Raf1 B-raf NFkB Rin RalBP “Exocist” Stat3 RalGEF Ral JNK Jun PI-3K Cell cycle control Tiam PIP3 AFX FKHR FKHR-L1 p27 p130 PKB Rac PTEN Cytoskeleton GSK3 Survival PDK Bad FasL Bim MnSOD eNOS Ras activates multiple pathways EGF PDGF LPA Insulin TCR Etc. Etc. Etc. Shc R Grb2 Ras SOS
- 25. PI-3 kinase phosphorylates PIP2 Figure 6.16b The Biology of Cancer (© Garland Science 2007)
- 26. One of the proteins is PKB (also known as Akt) Fosforylatie door PDK’s maakt PKB actief en vrij Figure 6.19a The Biology of Cancer (© Garland Science 2007)
- 27. PI3,4,5P3: Translocatie van Protein Kinase B (PKB) en PDK1 (kinase) PDK1: Activatie van Protein Kinase B (PKB)