Tyrosine Kinases

Question 1

What are the characteristics of Tyrosine Kinase Receptors?

Answer 1

• 60 genes encode human RTK’s
• 16 structural subfamilies
• Single transmembrane proteins
• Extracellular ligand binding domain
• Intracellular tyrosine kinase domain

Question 2

What is the Tyrosine Kinase structure similar to?

Answer 2

Antibodies - immunoglobin like domains

Question 3

How does RTK receptor activation work?

Answer 3

• Ligand binds to extracellular binding site
• Causes the receptor chain to dimerize
• Phosphorylate tyrosine residues on cytosolic domain -autophosphorylation

Question 4

What do the phosphorylated groups do?

Answer 4

Act as a scaffold for the binding of various different tyrosines - very specific

Question 5

What is PDGF receptor?

Answer 5

A receptor that has 5 phosphotyrosine docking sites, to which 3 different signalling proteins can bind
SH2 - Src homology region 2
SH3 - bind to proline rich regions

Question 6

How is the signal relayed through the cytoplasm?

Answer 6

2 ways

1) Docking protein may become phosphorylated and in turn activate next protein in pathway
2) Docking protein may move closer to next protein in signalling pathway and cause it to be activated

Result is to propagate the signal through the cytoplasm and into nucleus

Question 7

What is the MAP kinase pathway?

Answer 7

MAP = mitogen-activated protein

GRB2 binds to a specific phosphotyrosine on EGFR and to cytosolic Ras GEF. Brings it nearer to the plasma membrane where Ras GEF promotes the formation of Ras GTP

Question 8

What is the pathway after Ras GTP is formed?

Answer 8

• Activates MAP-kinase-kinase-kinase
• This is phosphorylated twice to for MAP-Kinase
• MAP kinase can bind to certain proteins in the cell and affect expression of certain genes

All molecules are bound to scaffold protein so that the chain reaction can occur quickly

Question 9

How is the signal removed?

Answer 9

• Dephosphorylation of tyrosine residues on RTK

- Endocytosis of receptor

Question 10

What is the importance of Ras?

Answer 10

30% of all human tumors contain mutations in ras
3 Ras genes in humans
-Some cancers have very high incidence of Ras mutations

Ras is a GTPase or G Protein

Question 11

What does Ras do?

Answer 11

Ras activates a number of signalling pathways involved in cell growth
-Activate genes in cell proliferation, leading to uncontrolled cell growth

Question 12

How can Rad be treated?

Answer 12

Treatments that don’t work:

• Target Ras directly (Ras activates too many signalling pathways so would kill a person)
• Target GEFS/GAPS (GTP binds so tightly to Ras that it is impossible to find a competitive inhibitor to replace
• Target downstream proteins (so many to choose from)

Question 13

What are the common steps in a signalling pathway?

Answer 13

• Scaffold or adaptor proteins may bring components together
• Signals may be amplified by secondary messengers or Kinases
• Signals may be integrated to spread to different pathways
• Components may be anchored to plasma membrane
• Cross talk may modulate the activity of a transduction pathway