1. 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

2. Nuclear receptor superfamily:
- signals differ in structure
- receptors similar, bind directly to DNA
- orphan nuclear receptors: ligand unknown

3. 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

4. 3) enzyme-linked:
- single-pass transmembrane proteins
- enzymes are protein kinases
4) other:
- receptors activated by regulated proteolysis

5. 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

6. 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)

7. 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

8. - cAMP activates protein kinase A (PKA), releases catalytic subunits
- catalytic subunits go to nucleus, regulate gene transcription

9. 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

10. Classes of enzyme-linked receptors:
1. Receptor tyrosine kinases
- signals (secreted factors, cell-surface-bound molecules) bind extracellular domains
- intracellular tyrosine kinase domain

11. Receptor tyrosine kinases are activated by cross-linking and cross-phosphorylation:
- ligands bind directly (A)
- ligands bind in clusters to proteoglycans (B)

12. Receptor tyrosine kinases are activated by cross-linking (cont.):
- ligands are clustered in plasma membrane (C)

13. 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

14. 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)

15. Enzyme-linked receptors (cont.):
2. cytokine receptors
- associated with cytoplasmic Jaks

16. - phosphorylated STATs dissociate from receptor, dimerize, bind directly to DNA

17. Enzyme-linked receptors (cont.):
3. receptor-like tyrosine phosphatases (ligands unknown)

18. Enzyme-linked receptors (cont.):
4. receptor serine-threonine kinases

20. 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

21. Signaling via regulated proteolysis: 1. Notch pathway

23. Signaling via regulated proteolysis: 2. Wnt pathway

24. Signaling via regulated proteolysis: 3. Hedgehog pathway

25. Signaling via regulated proteolysis: 4. NF-KB pathway