Signalling in Metabolic Regulation

Question 1

Describe the major features of enzyme-linked receptors

Answer 1

Predominantly single transmembrane domain receptors- a single pp which spans the membrane once
Activation leads to activation of receptor kinases
Activation leads to the activation of multiple signalling pathways

Question 2

Enzyme linked receptors are involved in…

Answer 2

Involved in the regulation of:
Cell growth
Division
Differentiation
Survival
Migration
Inappropriate receptor activity is associated with disease inc cancer

Question 3

Enzyme linked receptors have and active and inactive form. Describe these

Answer 3

Inactive- nothing bound to the receptor
Active- signalling proetins crosslink receptor chains, allowing the receptor to undergo a conformational change
Dimerisation allows phosphorylation to occur

Question 4

How does dimerisation and phosphorylation allow proteins to get activated?

Answer 4

Dimerisation brings 2 receptor molecules juntos, allowing auto-phosphorylation of specific tyrosine residues

Not all tyrosine residues can be phosphorylated, and are identified by the surrounding aa

The phospho-tyrosine together with surrounding amino acids are recognised by SH2 domains of other proteins allowing them to bind and undergo activation

Question 5

Explain how the insulin receptor can regulate several functions in a single cell

Answer 5

Alpha and beta chains are crosslinked in an insulin receptor
Binding of insulin to the insulin receptor brings the chains juntos, allowing phosphorylation
Signalling pathways is activated by recruiting IRS
1 pathway activated is activated PI3-kinase which evetially forms PKB. This is involved in glycogen and protein synthesis

Question 6

How are signal pathways terminated/inactivated?

Answer 6

Kinases add phosphates. Phosphatases remove phosphates
Receptor activation is from phosphorylation, so de-phosphorylation leads to inactivation.

Phosphatases are activated as a result of the receptor activation.
Therefore the signalling process is also involved in signal termination
PTEN removes the phosphates from the kinase and inhibits further activity

Question 7

What is Ras?

Answer 7

• Ras is a G-protein similar to Gαs that has inherent GTPase activity which leads to the hydrolysis of GTP to GDP
• The Ras GTPase activity is greatly enhanced by GTPase activating protein (GAP)

Question 8

Describe the role of JAK/STAT in growth hormone receptor signalling

Answer 8

Activation of Jak2 by cross phosphorylation leads to phosphorylation of a gene expression regulator called STAT
STATs dissociate from the receptor and dimerize via SH2 domain
This stable dimer has a strong affinity for specific DNA binding sites and regulates gene expression

Question 9

How does TGFβ regulate transcription?

Answer 9

TGFβ is a serine/threonine receptor kinase and activates SMADs
TGF-β binds to type II. The activated type II recruits type I. This phosphorylates the serine residues and forms an activated receptor.
Activated type I receptor then binds a Smad protein which it phosphorylates on a serine residue.
Phosphorylated Smad then dissociates from the receptor and complexes with Smad4.
This complex migrates to the nucleus where it will interact w transcription factors