Receptor tyrosine kinase

Question 1

What are receptor tyrosine kinases (RTK)?

Answer 1

cell surface receptors

Question 2

What are the ligands for RTKs?

Answer 2

soluble or membrane bound peptide/protein hormones

e.g. nerve growth factor, platelet derived growth factor, fibroblast growth factor, epidermal growth factor, insulin

Question 3

Broadly, what happens when a ligand binds to RTK?

Answer 3

• stimulates the receptor’s intrinsic protein-tyrosine kinase activity
• stimulates a signal-transduction. cascade -> functions like cell proliferation and differentiation, promotion of cell survival

Question 4

What RTK has been identified in breast cancer?

Answer 4

neu locus mutation

Question 5

What specifically happens to RTK when a ligand binds (molecularly)?

Answer 5

• RTKs dimerize

- autophosphorylation leading to conformational changes facilitating binding of ATP or proteins

Question 6

What is Ras?

Answer 6

• GTP-binding switch protein

- alternates between an active on state with a bound GTP and an inactive off state with a bound GDP

Question 7

What protein accelerates Ras activation?

Answer 7

GEF (guanine nucleotide exchange factor)

• activated by ligand binding to RTK
• binds to Ras-GDP complex and causes dissociation of bound GDP

Question 8

What is EGFR?

Answer 8

a receptor tyrosine kinase that is a receptor for epidermal growth factor
- key downstream effect -> Ras activation

Question 9

What are the steps for EGF/EGFR mediated Ras activation?

Answer 9

• hormone binds causing dimerization and phosphorylation of cytosolic receptor tyrosine residues
• SH2 domains on proteins bind to phosphotyrosine
• GDP released and replaced with GTP on Ras
• Ras activated and signals

Question 10

How does GAP regulate Ras signaling?

Answer 10

Inactivates - takes of phosphate

Ras-GDP

Question 11

How does GEF regulate Ras signaling?

Answer 11

Activates - exchanges GDP for GTP

Question 12

What two proteins are involved in Ras activation?

Answer 12

• Grb2 (adaptor)

- Sos (GEF)

Question 13

Is Sos targeting to the plasma membrane sufficient to activate Ras even in the absence of RTK stimulation?

Answer 13

yes

Question 14

How are EGFRs (HER1,2,3,4) related to cancer?

Answer 14

• increased EGFR correlates with poorer clinical outcomes in breast, lung, head, and neck cancer
• increased receptor associated with increased production of ligands (autocrine stimulatory pathway)

Question 15

How does anti-EGFR certuximab work?

Answer 15

Blocks ligand binding

Question 16

How do anti-EGFR antibodies work?

Answer 16

block ligand binding and prevent receptor dimerization

Question 17

How does Gefitinib work?

Answer 17

blocks EGFR kinase activity and stops downstream signaling

Question 18

Why does Geftinib work and then stop working?

Answer 18

• works in patients with EGFR point mutations

- secondary EGFR mutation are then selected in tumors that progress after treatment leading to resistance

Question 19

Are kinase inhibitors specific to just the target?

Answer 19

No, they often hit lots of targets