UnitD 2

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Cards (29)

  • Enzyme-coupled receptors

    • Display ligand binding domains on outer surface of plasma membrane
    • Can act as enzymes
    • Can bind other enzymes
  • Some receptors are activated by extremely low concentrations of ligands (10-9 – 10-11 M)
  • Growth factors and hormones
    Ligands that activate receptors at extremely low concentrations
  • Response to enzyme-coupled receptor activation
    • Slow (hours) since they alter gene expression
    • Involves phosphorylation of a downstream target or of the receptor itself
  • Receptor tyrosine kinases (RTKs)

    • Many enzyme-coupled receptors are tyrosine kinases
    • Have a single membrane spanning domain, unlike G-protein coupled receptors which have 7
  • Activation of RTKs

    1. Ligand binding induces aggregation of the receptors
    2. Followed by autophosphorylation (one receptor phosphorylates tyrosine residues of a neighboring receptor)
  • Activated RTKs

    • Recruit a complex of intracellular signaling proteins
    • Phosphorylated tyrosine residues serve as docking sites for intracellular signaling molecules
    • Binding of these molecules activates downstream signaling pathways and transduces the original extracellular signal
  • Intracellular signaling proteins

    • Possess several interaction domains that allow recognition of tyrosines on receptor tail or phosphorylated lipids in cytosolic monolayer of PM
    • The combination of interaction domains allows them to bind to both the enzyme-coupled receptors and each other
  • Ras

    • A common signaling complex protein
    • Small GTP binding protein attached to cytosolic tail
    • When bound to GDP it is inactive, when bound to GTP it is active
  • Ras activation

    1. Interaction with the activating protein, Ras GEF (Guanine Exchange Factor) allows Ras to exchange a GDP for a GTP
    2. Ras is then inactivated by Ras GAP (GTPase Activating Protein) where hydrolysis of GTP à GDP occurs = inactivation
  • The Ras-Raf-MAP kinase pathway
    1. EGF binds to its receptor
    2. EGF binding leads to binding of two enzyme-coupled receptors AND phosphorylation of the cytosolic tails of each receptor
    3. GRB2-Sos complex binds to the activated receptor through the SH2 domain of GRB2; Inactive Ras can then associate with Sos
    4. Sos the activates Ras by allowing it to release its GDP and bind GTP
    5. Ras-GTP binds to and activates Map kinase kinase kinase which in turn phosphorylates and activates Map kinase kinase
    6. Map kinase kinase then phosphorylates Map kinase
    7. The activated Map kinase protein will then activate effector proteins which will directly act to initiate a cellular response
  • RTKs activate Phosphoinositide 3-Kinase
    1. Survival signal IGF will bind to RTK and activate PI-3 kinase
    2. PI-3 kinase will then phosphorylate inositol phospholipid embedded in PM
    3. This phosphorylation in turn recruits signaling protein, Akt
    4. Akt is itself activated by protein kinases 1 and 2
    5. Activation of Akt promotes cell survival
  • Akt activation

    1. Akt (Protein Kinase B) phosphorylates Bad (protein that activates apoptosis) and inactivates it
    2. The inactive Bad protein then releases the bound Bcl2, thus signaling for cell to survive via apoptosis inhibition
  • Notch receptor activation

    1. Notch receptor binds signaling protein, Delta
    2. This bindings initiates cleavage of cytosolic tail of the receptor
    3. This cleaved Notch tail migrates to the nucleus where it will directly activate Notch-specific gene transcription
  • Some extracellular signal molecules cross the plasma membrane and bind to intracellular receptors
  • Enzyme-coupled receptors

    • Display ligand binding domains on outer surface of plasma membrane
    • Can act as enzymes
    • Can bind other enzymes
  • Some receptors are activated by extremely low concentrations of ligands (10-9 – 10-11 M)
  • Growth factors and hormones
    Ligands that activate receptors at extremely low concentrations
  • Response to enzyme-coupled receptors
    • Slow (hours) since they alter gene expression
    • Involves phosphorylation of a downstream target or of the receptor itself
  • Receptor tyrosine kinases (RTKs)

    • Many enzyme-coupled receptors are tyrosine kinases
    • Have a single membrane spanning domain, unlike G-protein coupled receptors which have 7
  • Activation of RTKs

    1. Ligand binding induces aggregation of the receptors
    2. Followed by autophosphorylation (one receptor phosphorylates tyrosine residues of a neighboring receptor)
  • Activated RTKs

    • Recruit a complex of intracellular signaling proteins
    • Phosphorylated tyrosine residues serve as docking sites for intracellular signaling molecules
    • Binding of these molecules activates downstream signaling pathways
  • Intracellular signaling proteins

    • Possess several interaction domains that allow recognition of tyrosines on receptor tail or phosphorylated lipids in cytosolic monolayer of PM
    • The combination of interaction domains allows them to bind to both the enzyme-coupled receptors and each other
  • Ras

    • Small GTP binding protein attached to cytosolic tail
    • When bound to GDP it is inactive, when bound to GTP it is active
    • Interaction with the activating protein, Ras GEF (Guanine Exchange Factor) allows Ras to exchange a GDP for a GTP
    • Ras is then inactivated by Ras GAP (GTPase Activating Protein) where hydrolysis of GTP à GDP occurs = inactivation
  • The Ras-Raf-MAP kinase pathway
    1. EGF binds to its receptor
    2. EGF binding leads to binding of two enzyme-coupled receptors AND phosphorylation of the cytosolic tails of each receptor
    3. GRB2-Sos complex binds to the activated receptor through the SH2 domain of GRB2; Inactive Ras can then associate with Sos
    4. Sos the activates Ras by allowing it to release its GDP and bind GTP
    5. Ras-GTP binds to and activates Map kinase kinase kinase which in turn phosphorylates and activates Map kinase kinase
    6. Map kinase kinase then phosphorylates Map kinase
    7. The activated Map kinase protein will then activate effector proteins which will directly act to initiate a cellular response
  • RTKs Activate Phosphoinositide 3-Kinase
    1. Survival signal IGF will bind to RTK and activate PI-3 kinase
    2. PI-3 kinase will then phosphorylate inositol phospholipid embedded in PM
    3. This phosphorylation in turn recruits signaling protein, Akt
    4. Akt is itself activated by protein kinases 1 and 2
    5. Activation of Akt promotes cell survival
  • Activation of Akt

    1. Akt (Protein Kinase B) phosphorylates Bad (protein that activates apoptosis) and inactivates it
    2. The inactive Bad protein then releases the bound Bcl2, thus signaling for cell to survive via apoptosis inhibition
  • Some Receptors Activate a Fast Track to the Nucleus
    1. Notch receptor binds signaling protein, Delta
    2. This bindings initiates cleavage of cytosolic tail of the receptor
    3. This cleaved Notch tail migrates to the nucleus where it will directly activate Notch-specific gene transcription
  • Some extracellular signal molecules cross the plasma membrane and bind to intracellular receptors