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Updated: Apr 9 2020

Signal Transduction

  • Tyrosine kinase signalling
    • Tyrosine kinase structure
      • dimeric transmembrane protein
      • intrinsic kinase activity
      • phosphorylated receptor can bind protein called insulin receptor substrate (IRS)
        • is a scaffold protein
    • Pathway
      • hormone binds to receptor
      • receptor is dimerized
      • auto cross-phosphorylation of intracellular domain of the dimerized receptor
      • IRS binds phosphorylated domian
      • IRS is phosphorylated on SH2-domains
      • several enzymes bind phosphorylated SH2-domians
        • phosphatases
          • pathway signaled for by insulin
        • kinases
          • phosphoinositol-3 (PI-3) kinase
        • G proteins
          • ras
            • oncogene present in many cancer
            • constitutive activation leads to constant growth signal
    • Examples
      • insulin, PDGF, EGF receptors
      • sensitization via PPAR-gamma
  • G protein signalling
    • G-protein structure
      • trimeric enzyme
        • α, β, γ
          • α-subunit has intrinsic GTPase activity
            • acts as timer for shutting off the active form
    • Pathway
      • hormone binds to receptor:G-protein complex on cell membrane
      • GDP bound to inactive α-subunit is exchanged for GTP
      • α-subunit now active
        • can be inhibitory (Gi) or stimulatory (Gs, Gq)
      • is released from β, γ subunits
      • can act as 2 different effector mechanisms
        • cAMP pathway
          • Gs activates adenyl cyclase
            • normally, ATP → cAMP to increase [cAMP]
            • cAMP can activate protein kinase A
            • Cholera and E. coli toxins
              • ADP-ribosylates subunit of Gs, which activates Gs
              • ↑↑↑ [cAMP]
          • Gi inhibits adenyl cyclase
            • normally, stops ATP → cAMP to decreases [cAMP]
            • Pertussis toxin
              • ADP-ribosylates subunit of Gi, which inhibits Gi
              • ↑↑↑ [cAMP]
        • PIP2 pathway
          • Gq activates phospholipase C
            • PIP2 → IP3 + DAG
              • DAG can activate protein kinase C
              • IP3 can release Ca2+ from the ER
                • Ca2+ then activates a number of enzymes including protein kinase C
      • GTP eventually hydrolyzed to GDP and α-subunit becomes inactive
    • Examples
      • cAMP = glucagon, epinephrine (β, α2)
      • PIP2 = vasopressin, epinephrine (α1)
      • full list given in G-protein-linked 2nd messengers topic
  • cGMP signalling
    • Pathway
      • hormone binds to receptor on cell membrane
        • there is also a soluble receptor in the cytoplasm
      • receptor has intrinsic guanylate cyclase activity
        • GTP → cGMP
          • cGMP activate protein kinase G
            • protein kinase G mediates smooth muscle relaxation/vasodilation
        • no G protein required
    • Examples
      • ANF → cell membrane receptor
      • NO → diffuses across cell membrane and binds soluble receptor
        • mechanism for pharmacologic nitrates (nitroprusside, nitroglycerine)
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