Receptor Tyrosine Kinases (RTKs)

Question 1

What do these receptors commonly mediate?

Answer 1

growth factors

Question 2

Describe the structure of RTKs

Answer 2

• Single pass with an intrinsic kinase cytosolic domain (catalytic)
• extrecellular region which binds to ligands
• One transmembrane alpha-helix
• Often dimerise (usually homodimers)

Question 3

Name two common ligands of RTKs

Answer 3

NGF - growth and differentiation of nerve cells

EGF - cell survival, growth and differentiation

Question 4

How are RTKs activated?

Answer 4

• Ligand binds to the receptor causes dimerisation of subunits (physically linked)
• Activates intracellular tyrosine kinase domain
• Cross phosphorylation of dimers results in the phosphorylation of multiple tyrosine residues

Question 5

How is the RTK signal transduced?

Answer 5

• Phosphorylation acts as binding site for downstream proteins
• Either SH2 or PTB domain binds to the phosphorylated tyrosine

Question 6

What is the difference between the binding of the SH2 and the PTB domain?

Answer 6

SH2 - binds directly to a receptor to mediate cellular events
PTB - binding of structural/platform proteins allowing for other signalling proteins to interact with te receptor

Question 7

What is the function of the RTK PI3-kinase?

Answer 7

Catalyses the conversion of PI2 to PI3 which mediates the binding of proteins to the membrane

Question 8

How is Akt(PKB) recruited and activated by PI3-kinase?

Answer 8

• Recruits inactive Akt/PKB to the membrane
• Akt is phosphorylated by PDK1 and PDK2 leading to full activation so that it can separate from the membrane and phosphorylate multiple downstream targets

Question 9

What happens when PKB is inactive?

Answer 9

Activates BAD (pro-apoptotic factor) which froms heterodimers BAD BCL-2 and BAD BCL- which promote cell apoptosis

Question 10

What happens when PKB is activated?

Answer 10

BAD is phosphorylated in 3 residues and goes on to form a dimer which causes it to stay in the cytosol, unable to promote apoptosis

Question 11

What is a Ras protein?

Answer 11

Is a GTPase which can hydrolyse GTP to GDP (where Ras GDP is inactive)

Question 12

How is the exchange of Ras GTP/GDP mediated?

Answer 12

• GEF catalyses the switching on, GAP catalyses the switching off
  e. g protein grb2 binds to phosphorylated tyrosine on the receptor and recruits protein sos1 which acts as a GEF (guanine exchange factor) which catalyses the activation of Ras protein

Question 13

How does Ras activate the mitogen-activated protein kinase?

Answer 13

Activate sequential phosphorylation mediated by kinases
MAPKKK (raf) phosphorylates MAPKK (MEK 1/2) which phosphorylates a MAPK (ERK 1/2) which phosphorylates trancription factors which regulate proliferation and survival