TKCRs and Intracellular Receptors

Question 1

What is the structure of TKRs?

Answer 1

• Membrane receptors that attach phosphates to tyrosines
• Can trigger multiple signal transduction pathways at once
• Occur in pairs and form a cross-linked dimer when ligand binds
  
  • unphosphorylated > phosphorylated
    
    • protein kinase uses ATP to transfer phosphate

Question 2

What are the functions of TKRs?

Answer 2

• Functions:
  
  • cell proliferation, differentiation
  • cell survival
  • cellular metabolism

Question 3

What is the activation of EGFR?

Answer 3

• Apoptosis: regulated cell death
• Proliferation: tissue growth
• Invasion: movement of cancer cells into healthy tissue
• Metastasis: spreading of tumour throughout the body
• Angiogenesis: growth of new blood vessels to supply tumour with blood

Question 4

Cell Cycle

Answer 4

Question 5

Intrinsic Kinase Activity: Kinase is part of the receptor

Answer 5

• Typical receptor tyrosine kinase receptor binds to its ligand resulting in dimerisation and self activation
• Activated receptor/ligand complex leads to the further activation of phosphorylated tyrosine residues on its target proteins

Question 6

Extrinsic Tyrosine Kinase Activity: The receptor is not an enzyme by itself, but rather it recruits these enzymes from the cytoplasm of the cell

Answer 6

• Cytokine-receptors must first dimerise and then bind to cytoplasmic tyrosine kinases before they are able to phosphorylate their target proteins
• Activated by cytokinesm interferons & HGF
• Activated receptor/ligand complex leads to further activation of phosphorylate tyrosine residues on its target proteins

Question 7

Discuss Insulin Receptor Activation

Answer 7

• Insulin binds to its receptor (tyrosine kinase linked), which causes many protein activity cascades
  
  • translocation of Glut-4 transporter to the plasma membrane
  • influx of glucose
• One of the reasons for insulin-resistant diabetes is improper function of insulin receptor

Question 8

What are ways of pharmalogical blocking of TKRs?

Answer 8

• Extracellular mAb inhibitors: mAbs
  
  • preventing growth factor from binding to the receptor
• Tyrosine kinase inhibitors: intracellular small molecules
  
  • preventing the phosphorylation and initiation of the process, ligand will bind but the signal will not occur

Question 9

What is the effect of TKIs on tyrosine kinases?

Answer 9

Blocking them stops the cell from growing and dividing

Question 10

What are the differences between single TKIs and multi TKIs?

Answer 10

• Single TKIs: block one type of tyrosine kinases
• Multi TKIs: block more than one type of tyrosine kinases

Question 11

What is the molecular targets for TKIs?

Answer 11

Phosphorylated parts is the target for drugs and TKIs

Question 12

What are the characteristics of intracellular receptors?

Answer 12

• Positioned inside the cell, not on the membrane
• Works very slowly

Question 13

What are the actions of steroids?

Answer 13

• Anti-inflammatory, anti-allergic, immuno-suppressive actions
• Readily cross the membrane and activate receptors
  
  • create a hormone-receptor complex
• Can act as a transcription factor, turning on specific genes and responding to specific ligands