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Bos 18112009 1
 

Bos 18112009 1

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    Bos 18112009 1 Bos 18112009 1 Presentation Transcript

    • 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
    • Calcium wave in fertilized egg
    • Calmoduline: een veel gebruikt calcium "receptor"
    • "Dual regulation" van CaCM (calmodulin) kinase
    • Dual regulation of "multisubunit" phosphorylase kinase
      Complex bevat eigenlijk vier subunits van elk
    • General structure Receptor tyrosine kinase
      Figure 5.9a The Biology of Cancer (© Garland Science 2007)
    • Many different types of RTKs: different ligand binding sites
      Figure 5.10 The Biology of Cancer (© Garland Science 2007)
    • Many different types of RTKs: different but overlapping intracellular docking domains
      Figure 6.9 The Biology of Cancer (© Garland Science 2007)
    • 1. Ligand binding
      2. Dimerisatie
      3. Activatie kinase
      4. Kruisfosforylering
      General principle of activation
      Dimerisation + activation
    • Sometimes the kinase is associated
    • Tyrosine gefosforyleerde receptor fungeert als "docking site" voor signalerings enzymen
    • Signaleringsroutes: vorming van eiwit complexen via specifieke eiwit-domeinen
    • Adaptor eiwitten bevatten vaak meerdere “herkenningsdomeinen”
    • Receptor tyrosine kinases maken vaak gebruik van specifieke membraan-gebonden "docking proteins"
    • 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
    • Ras, a molecular switch
      GDP
      GEF
      GTP
      Ras
      Ras
      Effector
      GAP
      Mutated in tumors
      vvvvvv
      GEF:
      guanine nucleotide exchange factor
      GAP:
      GTPase activating protein
    • Mechanism of Ras activation by guanine nucleotide exchange factor
    • Mechanism of Ras inactivation by
      GTPase activating protein
      Mechanisme van GAP geinduceerde hydrolyse
    • Visualisation of Ras activation by FRET
      FRET
      (fluorescent resonance energy transfer)
      Mochizuli et al., Nature , 411 (2001) 1066
    • 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
    • Many stimuli can activate
      Ras by different mechanisms
    • 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
    • PI-3 kinase phosphorylates PIP2
      Figure 6.16b The Biology of Cancer (© Garland Science 2007)
    • 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)
    • PI3,4,5P3: Translocatie van Protein Kinase B (PKB)
      en PDK1 (kinase)
      PDK1: Activatie van Protein Kinase B (PKB)