Bos 18112009 1

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Bos 18112009 1

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

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