480 likes | 1.18k Views
OVERVIEW: Signals for cell surface receptors (hydrophilic): - membrane-bound (contact-dependent signaling) - released into extracellular space - local (paracrine) or long-distance (endocrine) signaling Signals for intracellular receptors (hydrophobic, on carrier proteins):
E N D
OVERVIEW: Signals for cell surface receptors (hydrophilic): - membrane-bound (contact-dependent 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, calmodulin-dependent 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