Signal transduction and cancer

Question 1

What are the 4 main forms of intracellular signalling?

Answer 1

• contact-dependent
• paracrine
• endocrine
• autocrine

Question 2

What are the general rules of signal transduction?

Answer 2

• pathway activation is rapid and transient
• persistant activation of a signalling pathway may lead to uncontrolled cell proliferation
• pathways are multi-component. Intracellular signalling molecules can compromise proteins, small molecules or lipids
• target proteins are post-translationally modified and this results in conformational changes

Question 3

What are post-translational modifications?

Answer 3

• acetylation
• methylation
• lipid conjugation
• ubiquitnation
• failure to inactivate a singling pathway = uncontrolled cell proliferation = cancer

Question 4

Describe signal specificity

Answer 4

• different ligands bind their own specific receptors
• the same ligand can induce a different response in different cell types because : the same ligand can bind diff receptors, or same receptor utilises diff intracellular signalling molecules to transmit the signal

Question 5

What are the different types of receptors?

Answer 5

• intracellular

- transmembrane - ion channels, GPCR, tyrosine kinase, Ser/Thr kinase

Question 6

What are some common regulatory elements?

Answer 6

• NF-KB triggered by immune stress
• CREB triggered by cyclic AMP
• Oestrogen receptor triggered by oestrogen
• ISGF3 triggered by interferon

Question 7

What are some downstream effectors from GPCR?

Answer 7

• glycogen breakdown
• ion channel regulation
• transcriptional activation (CREB)
• Ca2+ influx/muscle contraction
• cytoskeleton rearrangements
• phospholipase C pathway (PIP2, DAG, IP3…)

Question 8

What happens in the RTK pathway?

Answer 8

• ligan binds to receptor
• receptor dimerisation
• due to close proximity of receptors = receptor-associated tyrosine phosphorylation
• effector protein recruitment = SH2 binds to phosphate
• receptor phosphorylates SH2
• phosphorylated SH2 detaches from receptor = downstream activity

Question 9

What is GEF?

Answer 9

• guanine exchange factor

- exchange GDP for GTP = active

Question 10

What are some mutations in receptors?

Answer 10

overexpression
- EGFR : most carcinomas
- ERBB2: 30% breast cancer
mutations that result in constitutively active:
- RAS: 20-30% human tumors
- 90% pancreatic adenocarcinoma
- 50% colon and thyroid adenocarcinoma
- BRAD: 7% human tumours
- 70% melanomas
- Ras and Raf are proto-oncogenes

Question 11

What happens in Akt/PKB signalling

Answer 11

• signal = receptor tyrosine kinase binds to complex = p85 + PI3K p110
• recruitment leads to phosphorylation of PIP2 –> PIP3
• PIP3 recruits another kinase = PDK1/2
• as a result of this= leads to activation of kinase = AKT/PKB
• AKT phosphorylates and inactivates GSK3 (regulates expression of cyclin D in cell cycle)
• AKT can also phosphorylate and inactivate Bad (involved in apoptosis)
  PTEN - removes phosphates - converts PIP3 back to PIP2

Question 12

What mutations affect the AKT/PKB pathway?

Answer 12

over-expression of RTK
mutations in PI3K (always active-even if not bound)
mutations in AKT (promote cell proliferation)
mutation in PTEN = inactivate, no longer able to dephosphorylate PIP3