6 - Signal Transduction Pathways

Question 1

Signal transduction

Answer 1

• The process by which a cell converts an extracellular signal into a cellular response
• LEads to alterations in cellular activity (proliferation, apoptosis, metabolism etc)

Question 2

What is signal transduction involved in

Answer 2

• Cell response to environment
• Cell to cell communication
• Intracellular homeostasis

Question 3

Essential Signal Transduction Pathway Components

Answer 3

• Ligand (extracellular signal)
• Receptor (what the ligand binds)
• 2nd messengers (relay message from signal to target)
• Targets

Question 4

Ligands

Answer 4

• Growth factors (e.g. TGF-α/β)
• Neurotransmitters (e.g. epinephrine)
• Hormones (e.g. androgens)
• Cytokines (e.g. chemokines)

Question 5

Receptors

Answer 5

• Cell surface receptors (tyrosine kinase receptors)
• Intracellular receptor (hormone receptors e.g. ER)

Question 6

2nd messengers

Answer 6

cAMP, kinases

Question 7

Targets

Answer 7

Transcription factors, translation factors, chaperones, actin/myosin filaments, enzymes

Question 8

JAK-STAT signalling

Answer 8

• Many cytokine receptors use non-receptor tyrosine kinases called JAKs to phosphorylate transcription factors called STATs
• The recruited STAT is activated by JAK phosphorylation, dimerizes, enters the nucleus, and turns on the expression of cytokine target genes

Question 9

The EGF-Receptor (HER2) Family

Answer 9

• Family members are over-expressed of have activating mutations in breast, gastric and lung cancer.
• Two prominent pathways activated by the EGF/Her2 family of GF are the ras-raf-Erk and the PI3K/Akt
  pathways.
• Inhibitors of the signalling have been developed as either antibodies or tyrosine kinase inhibitors

Question 10

One common pathway activated by many cell activators that promote cell proliferation (a hallmark
of cancer)

Answer 10

The ras-raf-Erk pathway

Question 11

True or False, Ref is only activated by Ras

Answer 11

FALSE

Question 12

The ras-raf-Erk pathway

Answer 12

• Different components of the pathway are mutated in different cancers
• i.e. in most lung cancers there are high levels of EGFR (right at the top of the pathway), while in melanoma there is a common activation of raf (specifically B-raf).
• So targeting down-stream of raf would potentially be widely applicable to many cancers

Question 13

Ras mutation

Answer 13

Pancreatic cancer

Question 14

full ras raf Erk pathway

Answer 14

• Ras –> RAFs –> MEK1/2 –> ERK1/2 –> ETS
• Most successful drug targets MEK1/2

Question 15

Targeting ras-raf-Erk pathway in melanoma

Answer 15

• Activated RAS –> BRAF –> MEK –> ERK –> Normal cell proliferation and survival
• BRAFV600 –> MEK –> ERK –> increased cell proliferation and survival
• Vemurafenib targets BRAFV600

Question 16

How does resistance to therapies (e.g. vemurafenib) targeting the BRAFV600 in melanoma arise

Answer 16

• Due to amplification of BRAF so much that the drug is insufficient to get into quantities able to inhibit all of it
• Truncation of BRAF so the drug will no longer bind
• Mutations downstream (in MEC), independent of BRAF
• Activation of other systems
• Reactivation of CRAF

Question 17

Specific functions of signalling circuits

Answer 17

• Motility circuits
• Cytostasis and differentiation circuits
• Viability circuits
• Proliferation circuits

Question 18

Central Player in the Viability Pathway of Cancer Cells.

Answer 18

Akt

Question 19

Akt

Answer 19

• Elevated survival signalling (Hallmark of cancer)
• Activated by many different upstream receptor systems and feeds into multiple downstream pathways.
• Also controls protein synthesis which is also a
  pathway targeted in cancer as the increased growth rate of cancer cells means they have to produce more protein.

Question 20

Akt inhibitor

Answer 20

Perifosine

Question 21

EGFR inhibitor

Answer 21

Erlotinib

Question 22

BCR-Abl inhibitors for CML

Answer 22

• The BCR-Abl fusion protein is a constitutively active kinase.
• A novel drug STI571/imatinib has been able to interfere with the kinase activity of BCR-Abl, inducing apoptosis in BCR-Abl+ cells by down regulating Bcl-X.
• The specificity of the drug is highest for the abnormal BCR-Abl kinase, and much less effective against normal
  kinases in the cell.
• The drug, therefore, targets the cause of the leukaemia

Question 23

Resistance to STI571/Imatinib

Answer 23

• Imatinib fits into the ATP binding pocket of wild-type BCR-Abl but when Threonine 315 is mutated to Isoleucine it can no longer fit as the Isoleucine protrudes into the space that part of the Imatinib would fit.
• Mg-ATP can still bind into the pocket so the T315I BCR-Abl is still active