Signal Transduction II

Question 1

General RTK mech

Answer 1

Phosphate onto tyrosine - charge and shape shift - changes fold - SH2 finds phosphorylated prtn. and acts as adapter - SH2 links to another protein - secondary singalling etc.

Question 2

Ligand binding domain

Answer 2

extracellular

Question 3

tyrosine kinase domain

Answer 3

intracellular

Question 4

when do receptors signal?

Answer 4

when they dimerize (sometime heterodimer with various partners)

Question 5

HIF

Answer 5

hypoxia induced factor

Question 6

What happens to HIF in normoxia?

Answer 6

Links with VHL and is marked for ubiquitination - degraded in proteosome

Question 7

What happens to HIF in hypoxia?

Answer 7

VHL cannot interact with HIF - no ubiquitination.
Results in translocation to nucleus
transcription factors for VEGF, PDGF

Question 8

Loss of VHL in ____ cancer

Answer 8

Kidney

too much VEGF - huge amount of proliferative signaling

Question 9

Potential solutions for VHL loss

Answer 9

Ab to soak up VEGF
TK inhibitors
Rapalogues (downstream) to keep the signaling from moving forward

Question 10

Downside of Rapalogues?

Answer 10

Potential for compensation pathways because further down stream in signaling cascade

Question 11

VEGF drugs

Answer 11

Sorafenib
Sunitinib
IFN/Bevacizumab
Pazopanib
Axitinib
(THINK -ibs)

Question 12

VEGF inhibitor side effects

Answer 12

Hypertension (marks on target toxicity)
Hypothyroidism
Loss of hair pigment
Rare/Lethal: GI perforation, Pericardial effusion, myelosuppresion, hepatic toxicity

Question 13

Her2 (Erb-B2)

Answer 13

EGFR family (Includes Her 1 -4), intracellular kinase activity but NO LIGAND BINDING DOMAIN

Question 14

Her2 + Her3

Answer 14

Heterodimerizes, HER3 has no intracellular kinase cascade so INHIBITS APOPTOSIS

Question 15

Her2 + EGFR

Answer 15

Heterodimerizes, PROLIFERATION

Question 16

Trastuzumab

Answer 16

humanized antibody to the extracellular domain of Her2

Question 17

TKI against Her2

Answer 17

Lapatinib. Blocks EGFR and Her-2

Question 18

Lapatinib side effect

Answer 18

diarrhea, nausea, etc.

Question 19

RTK and Lung cancer

Answer 19

5% of patients have EGFR activating mutation or ALK signaling
Young, female asian non smokers
del exon 19 L858R most likely to respond to directed therapy
T790M mutation resistant to target therapy

Question 20

TKI lung cancer

Answer 20

Gefitinib and Erlotinib