Signalling in Metabolic Regulation

Question 1

What are the main features of enzyme-linked receptors?

Answer 1

• Enzyme linked receptors are mainly single transmembrane domain receptors:
o Their activation leads to activation of receptor kinases and multiple signalling pathways.
o Involved in the regulation of cell growth/division/differentiation/survival/migration
o Inappropriate activation of these receptors is linked with cancer

Question 2

Outline the steps of Tyrosine Kinase Receptor (TKR) Activation

What is a G protein e.g. Ras?

Answer 2

1. Ligand binding = Dimerisation to bring 2 receptor molecules together to allow for phosphorylation of specific tyrosine residues = activation
2. Phosphorylated tyrosine resides bind to SH2 domains, which can produce other secondary messengers
3. Activation leads to the production of Ras protein (a small G protein)

• Are related to the Gα subunit:
  Inactive = bound to GDP
  Active = replaced by GTP, which is aided by GEF (Guanine nucleotide exchange
  factor)

*Involved in cell growth and differentiation.

Question 3

Outline the steps of Tyrosine Kinase Receptor (TKR) Inactivation

Answer 3

Since phosphorylation = activation, dephosphorylation = deactivation

• Receptor activation leads to the activation of Phosphatases, which will eventually inactivate the receptors by removing the phosphates - self limiting process
• Small G proteins have intrinsic GTPase activity
• Receptors can be internalised – removed from the cell surface

Question 4

How are Insulin receptors activated and what are the effects of it’s activation?

LOOK AT DIAGRAM!

Answer 4

• Consists of 2α and 2β subunits linked by disulphide bridges and has TYROSINE KINASE ACTIVITY
• Acts on the liver and muscle to ↓blood glucose
• Insulin binds = auto-phosphorylation of 2β subunits, as well as the activation of a family of small proteins, called IRS (Insulin Receptor Substrates).
• An effect is the activation of PKB, which goes on to phosphorylate other proteins – leads to ↑glycogen and protein synthesis, and the insertion of GLUT4 transporters

Question 5

How can mutations in key regulatory mechanisms lead to cancer using Epithelial Growth Factor (EGF) Receptors?

Answer 5

• Overexpression of EGF receptors = excessive activation
• ↓phosphate activity and ↓GTPase activity = prolonged activation of EGF receptor

• Antibodies can be used to target a specific type of EGF receptor to reduce activation/signalling

Question 6

Explain the JAK/STAT pathway in Growth Hormone (GH) receptors

LOOK AT DIAGRAMS!

Answer 6

GH binding = activation of JAK-STAT signalling pathway:
1. JAK (Janus Kinase) phosphorylates itself and tyrosine residues on the receptor

2. STAT (Signal transducer, activator of transcription) binds to the phosphorylated tyrosine residues, and is then phosphorylated by JAK
3. STATs dissociate from the receptors and dimerise/join before going into the nucleus = ↑specific gene transcription

Question 7

What are the similarities and differences between the activation of TGFβ and GH receptor signalling?

LOOK AT DIAGRAM!

Answer 7

TGFβ have a Serine/Threonine kinase domain:

• Receptor dimerisation occurs on activation → phosphorylation of Smad2/3 (instead of STAT)
• Phosphorylated Smad2/3 joins with Smad4 → goes into nucleus = ↑specific gene transcription (same as STAT)