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Transcript
OVERVIEW:
Signals for cell surface receptors
(hydrophilic):
- membrane-bound (contactdependent signaling)
- released into extracellular space local (paracrine) or long-distance
(endocrine) signaling
Signals for intracellular receptors
(hydrophobic, on carrier proteins):
- pass directly through plasma
membrane
- receptors in cytosol or nucleus
Nuclear receptor superfamily:
- signals differ in structure
- receptors similar, bind directly to DNA
- orphan nuclear receptors: ligand unknown
4 classes of cell surface receptors:
1) ion-channel-linked:
- bind neurotransmitters
- synaptic signaling
2) G-protein-linked:
- 7-pass transmembrane proteins
- bind trimeric G-proteins
3) enzyme-linked:
- single-pass transmembrane proteins
- enzymes are protein kinases
4) other:
- receptors activated by regulated proteolysis
Overview of signal transduction:
- intracellular signaling proteins, second
messengers relay the signal
- scaffold proteins (multiple PDZ or other
domains), lipid rafts (thicker membrane
regions) organize signaling proteins into
complexes
G-protein-linked receptors:
1. active receptor binds G-protein,
GDP exchanged to GTP
3. G-protein breaks into GTP-a and
bg; both can activate target proteins
4. GTP hydrolyzed to GDP, a and
bg reassemble
RGS proteins regulate signaling
(GAP activity - GTP to GDP in a
subunit)
Some G-proteins signal via cAMP:
- Gs (stimulatory) activates adenylyl
cyclase
- Gi (inhibitory) inhibits adenylyl
cyclase
Two bacterial toxins act via Gs,Gi:
- cholera: a subunit of Gs altered,
can’t hydrolyze GTP
- pertussis: a subunit of Gi altered,
can’t exchange GDP
- cAMP activates
protein kinase A
(PKA), releases
catalytic subunits
- catalytic subunits
go to nucleus,
regulate gene
transcription
Some G-proteins signal via
PI(4,5)P2:
- Gq activates phospholipase C-b
- PI(4,5)P2) cleaved into IP3 and
DAG
- IP3 opens gated Ca++ channels
Kinases regulated by Ca++ (and
DAG):
- protein kinase C (PKC)
- calmodulin, calmodulindependent protein (CaM) kinases
phosphatidylinositol
4,5-bisphosphate
Classes of enzyme-linked receptors:
1. Receptor tyrosine kinases
- signals (secreted factors, cell-surface-bound molecules) bind extracellular domains
- intracellular tyrosine kinase domain
Receptor tyrosine kinases are activated by cross-linking and cross-phosphorylation:
- ligands bind directly (A)
- ligands bind in clusters to proteoglycans (B)
Receptor tyrosine kinases are activated by cross-linking (cont.):
- ligands are clustered in plasma membrane (C)
Signaling via P-tyrosines (P-Y): formation of a signaling complex
- proteins with SH2 or PTB domains bind P-Y
- some contain SH3 domains, which bind proline-rich motifs on other proteins
Some P-Y receptors signal via Ras:
- monomeric G-protein
- regulated by GEF and GAP
P-Y domains bind GEF via SH2,
SH3-domain proteins (adaptors):
- bound GEF stimulates Ras to
exchange GDP for GTP
Active Ras stimulates downstream signaling
pathways:
- MAP kinase pathway (cell proliferation)
- PI3 kinase pathway (cell growth)
Enzyme-linked receptors (cont.):
2. cytokine receptors
- associated with cytoplasmic Jaks
- phosphorylated
STATs dissociate
from receptor,
dimerize, bind
directly to DNA
Enzyme-linked receptors (cont.):
3. receptor-like tyrosine phosphatases
(ligands unknown)
Enzyme-linked receptors (cont.):
4. receptor serine-threonine kinases
Enzyme-linked receptors (cont.):
5. Receptor guanylyl cyclases (cGMP formation,
cGMP-dependent kinase)
6. Histidine kinase receptors
- in bacteria and plants, unrelated to all others
Signaling via regulated proteolysis: 1. Notch pathway
Signaling via regulated proteolysis: 2. Wnt pathway
Signaling via regulated proteolysis: 3. Hedgehog pathway
Signaling via regulated proteolysis: 4. NF-KB pathway