Targeting Cancer Cell Proliferation and Apoptosis

Question 1

Describe the receptor tyrosine kinase pathway?

Answer 1

1. In unstimulated state they exist as monomers
2. Growth factors binds to the receptor and causes dimerisation (close so can cross phosphorylation).
3. Leads to phosphorylation GATP –> GADP (amino-acid-tyrosine). This activates the kinase domains
4. Proteins bound to phosphorylated tyrosines get activated.
5. Phosphorylated tyrosine causes downstream signalling

Question 2

What is the role of adaptor proteins?

Answer 2

Important adaptor molecule in GF signalling is Grb2. This has 2 protein-protein interactions
- SH2: binds to phosphorylated tyrosine of the receptor
SH3: (2 copies): bind to the proline rich regions

Question 3

Describe the RPTKs signal to Ras?

Answer 3

• Grb2 bound to RPTK via its SH2 domain and binds to 2 protein called SOS through SH3 domains
• SOS = exchange factor for Ras (signalling molecule).
• RPTK becomes activated, phosphorylation of the receptor
• Gbr2 binds to these phosphorylated tyrosine domains –> SOS now close enough to membrane to activate Ras. SOS: GDP to GTP (GTP bound Ras).
• Confirmation changes of Ras
• -> activation –> downstream
• important the Ras protein binds with membrane to work.

Question 4

Describe the Ras signalling cycle.

Answer 4

• Ras is a GTP binding protein –> powerful molecular switches
• ON = GTP bound
• OFF = GDP bound
• GTP can replace GDP to make Ras active
• GTP binding protein protein is able to hydrolyse GTP to GDP to turn itself off
  -Hydrolysis can be stimulated by GTPase activating proteins (GAPs)
  -Cycle of GTP binding proteins almost always controlled by:
  
  • Exchange factors (e.g.) SOS = ON
  • GTPase activating proteins (GAPs) that
    turn it = OFF

Ras most commonly mutated in ways that causes Ras to be permanently switched on

Question 5

Describe the Ras activates a protein kinase cascade?

Answer 5

• Extracellular signal regulated kinase (Erk) cascade
• Mitogen - activated protein kinase (MADK) cascade
• GTP bound Ras binds to a kinase and then that kinase activates several other kinases -
• The top kinase phosphorylates the next kinase etc
• Kinase cascade involved in growth stimulatory signalling known as ERK casacade.
• The family of these kinases are called the mapk cascades.
  -Receptor tyrosine kinase and MAK are important in the G1 cycle
  G1 responds to extracellular environment.