1. Chapter 16 Cell Communication
The major signaling
pathways relevant
to cancer
You will not be responsible for:
Specific downstream
signaling pathways
Questions in this chapter you should be able to answer:
Chapter 16: all but e, 12,13,16,17,18, 19, 20, 22, 24, 25
Cell Communication

2. How do cells communicate with each other?
Signaling mechanisms
Signaling responses
Cell Communication

3. What types of molecules carry signals to cells?
1) Gases (really small)
NO, H2S, CO
2) ‘Smallish’ organic molecules
steroids
neurotransmitters
[drugs/poisons (nicotine, phytohormones, etc)]
3) Peptide hormones (much bigger)
EGF
Cell Communication

4. Where are the receptors?
Intracellular receptors vs
Cell-surface receptors
Cell Communication

5. How do cell surface receptors function?
Signal transduction
Pathways
Signaling proteins
Secondary Signals
-- cAMP, Ca++, DAG, IP3
FSH & Receptor
Cell Communication

6. Signaling pathways can interact
Multiple signals
Processed simultaneously
Activating or inhibiting
Signal integration
Cell Communication

7. What are the three types of cell surface receptors?
= Ligand-gated channel
Cell Communication

8. G-protein-linked receptors
How are G-proteins activated?
“7-pass” receptors
-- Hundreds of different types
-- triggering enumerable different
cytoplasmic processes
Examples
Glucagon – activates glucose release by liver
Lutenizing Hormone (LH) – triggers progesterone
release from ovary
Adrenalin (epinephrine) – increases heart rate
Allergen – mast cell degranulation
G-protein-linked receptors
Cell Communication

9. (a) A high concentration of a non-hydrolyzable analog of GTP.
Acetylcholine acts at a G-protein-linked receptor on heart muscle to make the heart beat more slowly by the effect of the G protein on a K+ channel, as shown in this Figure. Which one or more of the following would enhance this effect of acetylcholine? Explain.
(a) A high concentration of a non-hydrolyzable analog of GTP.
(b) Mutations in the acetylcholine receptor that weaken the interaction between the receptor and acetylcholine.
(c) Mutations in the G protein α-subunit that speed-up the hydrolysis of GTP.
(d) Mutations in the K+ Channel that make the βγ-subunit bind tighter
Cell Communication

10. How do activated G-proteins trigger release of ‘secondary messenger’ molecules?
-- open channels
-- activate enzymes
Secondary messengers include:
cAMP, Ca++, DAG, IP3
Some toxins interfere with G-proteins
Cholera toxin
Inhibits GTPase activity of α-subunit
-- causes Na+ efflux into intestine
-- water flow into intestine
Pertussis toxin
Prevents GDP/GTP exchange
-- GTP locked in off state
-- mucous secretion into lungs
cAMP Signaling
Cell Communication

11. Downstream effects can be
Downstream enzyme activation
(can be very rapid)
-- effect of adrenaline
Changes in gene expression
(slower)
There can be many other types of responses
Block gene expression
Activate exocytosis
-- allergic responses
-- insulin release
or endocytosis
-- phagocytic cells
Cell Communication

12. Δ Membrane potential Retina contains G-protein coupled light receptors
Rod cells
Activation ↓ Na+ flow
Na channel gated by cGMP
Rhodopsin
Transducin (G-protein)
-- activates cGTP phosphodiesterase
Δ Membrane potential
Question 16-8
P 556
Cell Communication

13. How do enzyme-linked receptors function?
Receptor Tyrosine Kinases (RTK)
Dimerization
Autophosphorylation
Activated signaling
proteins
Cell Communication

14. RAS activates a kinase “cascade” (MAP Kinase module)
RTK Signaling often
occurs through Ras
A “monomeric” GTP-binding protein
RAS activates a kinase “cascade” (MAP Kinase module)
Cell Communication

15. Signaling Pathways and Cancer
Oncogenes
-- Deregulated cell proliferation
-- mitogens and growth factors
Constitutive Activation/Signaling
RAS mutations are common in cancers
Cell Communication

16. How are complex signally pathways ‘dissected’?
Genetically engineer cells to contain…
-- Knockout mutations
-- Constitutive expression mutations
How do these 5 experiment establish signaling sequence of RAS, X and Y?
Cell Communication

17. When activated by the signal, the platelet-derived growth factor (PDGF) receptor phosphorylates itself on multiple tyrosines (as indicated below by the circled Ps; the numbers next to these Ps indicate the amino acid number of the tyrosine). These phosphorylated tyrosines serve as docking sites for proteins (A, B, C, and D) that interact with the activated PDGF-receptor. Binding of PDGF activates the PDGF-receptor leading to an increase in DNA synthesis. To determine whether protein A, B, C, and/or D are responsible for activation of DNA synthesis, you construct mutant versions of the PDGF-receptor that retain one or more tyrosine phosphorylation sites. In the cells, the various versions of the PDGF-receptor become phosphorylated on whichever tyrosines remain. You measure the level of DNA synthesis in cells that express the various mutant receptors and obtain the data shown below.
From these data, which, if any, of these proteins A, B, C, and D are involved in the stimulation of DNA synthesis by PDGF? Why?
Which, if any, of these proteins inhibit DNA synthesis? Why?
Which, if any, of these proteins appear to play no detectable role in DNA synthesis? Why?
What is the effect of the binding of A on the effect of B?
Cell Communication