Last Class:
A. intracellular vesicle traffic1. ER to golgi
2. endocytosis, exocytosis B. Signaling Transduction
1. Ligand Receptor Interactions, 2. Intracellular signaling molecules, 3. molecule switches:
phosphorylation and GTP binding, 4. Signaling integration, 5. complex formation, 6. Signaling
amplification, 7. Signaling desensitization
• Cell Communication
• Different Receptor Types• Ion channel-linked receptors• *GPCR signaling• *Enzyme linked receptors
The disassembly of G-Protein upon stimulation
Spontaneous deactivation is very fast, in minutes.
However, with the help of RGS (regulator of G
protein signaling, a GAP for unit), signals can be
shut off even faster
cAMP cycle: GPCR->Gs->adenylyl cyclase->cAMP
Cyclic AMP phosphodiesterase breaks down cAMP to 5’-AMP
Phospholipase C-
(PLC-) Produces DAG
(diacylglycerol) and IP3 (inositol 1,4,5-
trisphosphate (IP3))
Gq->PLC-
Fertilization of an egg by a sperm triggering an increase in cytosolic Calcium
3 major types of calcium channels:
1. Voltage dependent Ca channels on plasma membrane
2. IP3-gated Ca release channels on ER membrane
3. Ryanodine receptor on ER membrane
Calcium uptake and deprivation1. Na/Ca exchanger on plasma membrane, 2. Ca pump on ER
membrane, 3. Ca binding molecules, 4. Ca pump on Mitochondia
Calcium Frequency encoding signaling
strength
Local Ca blips, sparks, puffs, reflecting local opening of individual
channels in ER, strong local signal induces global activity, the
elevated Calcium trigger calcium deprivation
system
Ca2+/calmodulin dependent protein kinase (CaM-kinase)Memory function: 1. calmodulin dissociate after 10 sec of low calcium level; 2. remain active after calmodulin dissociation
Ca2+/calmodulin dependent protein kinase (CaM-kinase)Frequency decoder of Calcium oscillation
High frequence, CaM-kinase does not return to basal level before the second wave of activation starts
Desensitization of GPCR
1. Inhibitory structural alteration of receptor; 2. receptor internalization; 3. receptor degration
GRK (G protein-linked receptor kinase)
Arrestin takes to clathrin-coated pits and degradation
• GPCR Signaling Summary• 1. G-protein types• 2. cAMP and Calcium signaling
pathways• 3. desensitization
Enzyme-Linked Cell Surface Receptors
•*Receptor Tyrosine Kinase•*Tyrosine kinase associated receptors•*Receptor-like tyrosine phosphatase•*Receptor serine/threonine kinase•Receptor guanylyl cyclase•Histidine like associated receptor
Three ways in which signaling proteins can cross-link receptor chains
1. dimer, 2. monomer but brought together by proteoglycan, 3. cluster on membrane
The regulation of Ras activity, a famous downstream molecule of RTK responsible for
cancer development
The recruitment of signaling molecules with
PH domains to the plasma membrane during B cell
activation
One PI3K pathway
PH domain: pleckstrin homology domain
Another PI3K pathway to regulate cell migration
PI3K->PIP3->GEF->Rac->Wave->Arp2/3->Actin polymerization
Movie: chemotaxis, PI3K and cell migration
1. Tyrosine kinase associated receptors
Integrins: cell-extracellular matrix adhesionBinding to Src and FAK
• Enzyme-linked Receptor Signaling Summary
• 1. receptor types• 2. RTK and its signaling: Ras and PI3K• 3. Tyrosine kinase associated receptors
and Receptor-like tyrosine phosphatase• 4. Receptor serine/threonine kinase, TGF-
and Smad
1. Wnt Signaling pathwayLRP: LDL-receptor-related protein; GSK-3: glycogen synthase
kinase-3APC: adenomatous polyposis coli;