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Receptor tyrosine kinases.ppt

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Transcript

  • 1.
    • Introduction
      • Recruitment of kinases in signalling pathways
      • Consequences of protein phosphorylation
    • RTK family:
      • Classification & structure/function
      • RTK ligands
      • Receptor dimerization & autotransphosphorylation
  • 2.
    • RTK-mediated pathways:
      • Ras-Raf-MAP kinase pathway, use of dominant negative mutants to map pathway
  • 3.
    • Cell surface receptors recruit activity of protein kinases in two general ways:
      • Non-receptor tyrosine kinases : Receptors lacking self-contained kinase function recruit activities of intracellular protein kinases to the plasma membrane
      • Receptor tyrosine kinases : Possess an intrinsic tyrosine kinase activity that is part of the receptor protein. Examples include receptors for growth factors (PDGF, EGF, insulin, etc.)
  • 4.
    • Implicated in diverse cellular responses:
      • Cell division
      • Differentiation
      • Motility
    • At least 50 RTKs identified:
      • Subdivided into 10 subclasses based on differences within extracellular, ligand-binding domain of receptor
    • “ Oncogenic” RTK mutants exist:
      • erbB gene encodes an N-terminal truncated, constitutively active form of EGF receptor
  • 5.
    • Four common structural features shared among RTKs:
      • Extracellular ligand-binding domain
      • Single transmembrane domain
      • Cytoplasmic tyrosine kinase domain(s)
      • Regulatory domains
  • 6.  
  • 7.
    • Extracellular ligand-binding domain.
    • Cytosolic domain with tyrosine kinase (tk) enzyme activity.
  • 8. Regulatory domains
  • 9.
    • Typically small soluble proteins
    • Work in autocrine and paracrine manner
    • Dimerize (may aid in receptor dimerization)
    • Some RTK ligands membrane-bound
  • 10.
    • Ligand-induced RTK activation induces Receptor dimerization, leading to activation of catalytic domains
    • Receptor autotransphosphorylation:
      • Further stimulates kinase activity
      • Leads to phosphorylation of additional proteins involved in receptor signalling pathway
      • Provides “docking sites” for downstream signalling proteins (Grb2, PI3-kinase, phospholipase C  , etc.)
  • 11.  
  • 12.
    • SH2 domains: bind P-Tyr-containing sequences
    • SH3 domains: bind to pro-rich (PxxP) sequences
  • 13.  
  • 14.
    • Receptor tyrosine kinase mediated signal transduction
    • does not involve G-proteins
    • does involve phosphorylation of proteins
    • … at tyrosines
  • 15. ligands inactive tyr kinase monomer … cross-phosphorylation of tyrosines Receptor Tyrosine Kinase Activation ATP ADP Phosphorylated tyrosines on activated signaling proteins  cell response active tyr kinase dimer P- P- P- -P -P -P X X X
  • 16. ligands inactive tyr kinase monomer cross-phosphorylation of tyrosines MAP ( mitogen-activated protein ) kinase activation: ATP ADP active tyr kinase dimer GDP GTP Ras inactive active MAP kinase-kinase-kinase active nucleus P- P- P- P- P- -P -P -P X X X adaptor protein Ras-activatingprotein MAP kinase-kinase MAP kinase translocation to nucleus…
  • 17. P | nucleus P- P- MAP kinase Transcription factors Other nuclear proteins DNA binding Changes in protein activity changes in gene activity Cell proliferation, differentiation
  • 18.
    • Ras-Raf-MAP kinase pathway
    • R7 photoreceptor development in drosophila (fruitfly)
  • 19. Tyr-P Grb2 SH3 domains Proline-rich regions (-PXXP-) Sos Ras (inactive) Pi Ras (active) Raf MEK MAP kinase P P P Nucleus MAP kinase P P fos jun P P Increase gene expression SH2 domain GDP GTP DNA
  • 20.
    • Regulates cell growth and cell reproduction
    • Tyrosine kinase catalyzes transfer of phosphate group from ATP to to tyrosines
    • Can trigger ten or more signal transduction pathways at once
    • Abnormal tyrosine kinases that work even without a signal molecule may contribute to some cancers
    • See next slide