13. Receptor Theories 2

Question 1

Describe the process of signal transduction.

Answer 1

Extracellular ligands regulate intracellular processes –> cellular response
* one ligand may bind to different receptors and mediate different intracellular changes.

Question 2

What is the difference between first versus second messenger?

Answer 2

First messenger - the extracellular ligand that binds a receptor
Second messenger - an intracellular small molecule that changes as a result of ligand binding –> triggers a response

Question 3

What occurs after the second messenger changes as a result of ligand binding?

Answer 3

Kinase cascades and transcriptional changes change the protein content of the cell –> changes the function of the cell

Question 4

What are the three classes of second messengers?

Answer 4

Hydrophobic molecules
* membrane associated (located on the membrane)

Hydrophilic molecules
* cytoplasmic (diffuse in the cytosol

Gases
* membrane/cytoplasm

Question 5

Describe the Protein Kinase A/CREB pathway.

Answer 5

• receptors bind ligand and activates adenylate cyclase
• ATP is converted to cAMP
• cAMP binds to PKA –> induces a conformational change –> activates signaling
• enters the nucleus
• A series of phosphorylations lead to activation of the CREB transcription factor (regulates cellular responses)

Question 6

Explain a selective vs non-selective ligand

Answer 6

Selective ligand - one ligand binds only one target and vice versa

Non-selective - one ligand binds multiple targets or one target binds multiple ligands

Question 7

How does ligand binding to growth factor receptors cause signal transduction?

Answer 7

• ligand binding induces phosphorylation of the receptor’s intracellular domain (ex. tyrosine)
• phosphorylated residues can be binding sites for cytoplasmic proteins (signals downstream)
• cytoplasmic proteins induce a signaling cascade –> cellular responses

Question 8

What are the structural properties of receptor tyrosine kinases?

Answer 8

• extracellular N-terminal region (for ligand binding)
• intracellular C-terminal region (catalytic - catalyzes receptor autophosphorylation and tyrosine phosphorylation of other substrates)

Question 9

What do tyrosine kinases do?

Answer 9

tyrosine kinases transfer a phosphate from ATP to a tyrosine residue in a* signaling protein*

Question 10

Can receptor tyrosine kinases share cellular responses?

Answer 10

Yes. Different receptors can share the same downstram results.

Question 11

Explain how Cetuximab works against various cancers.

Answer 11

• binds to extracellular domain of EGFR (epidermal growth factor receptors)
• blocks ability of EGF to bind EGFR (antagonist)
• prevents extended conformation
• inhibits dimerization and autophosphorylation

Question 12

What is Erlotinib?

Answer 12

reversible competitive inhibitors of EGFR receptors

Question 13

In the presence of EGF ligand, the Ki for erlotinib binding is ____ than in the absence of EGF.

Answer 13

Lower

Question 14

Explain the steps of VEGF pathways.

Answer 14

What: set of pathways that recruits blood vessel formation.
How:
* VEGF binds to VEGFr
* increases activity of phospholipase C –> increases IP3 concentrations
* IP3 releases Ca2+ from intracellular stores
* Ca2+ stimulates transcription via NFAT transcription factor
* Dephosphorylation of NFAT by phosphatase calcineurin –> cell proliferation/angiogenesis
(when NFAT gets dephosphorylated by calcineurin –> cell proliferation)

Question 15

Explain the use of cyclosporine.

Answer 15

• immunosuppressant
• prevents dephosphorylation of NFAT (which prevents transcription of genes –> prevents cell proliferation)

Question 16

What is the role of NFAT? What happens if it is phosphorylated or dephosphorylated?

Answer 16

NFAT gets dephosphorylated by calcineurin –> cell proliferation

When NFAT can’t get dephosphorylated –> prevention of cell proliferation