Receptor Mechanism III Flashcards
What are enzyme linked receptors?
Predominantly single transmembrane domain receptors
Activation leads to activation of receptor kinases
Activation leads to activation of multiple signalling pathways
Involved in:
Cell growth
Division
Differentiation
Survival
Migration
Inappropriate receptor activity is associated with disease including cancer
Signalling proteins cross-link receptor chain
How are enzyme linked receptors activated?
Dimerisation brings together two receptor molecules allowing auto-phosphorylation of specific tyrosine residues
Not all tyrosine residues can be phosphorylated
Phosphorylation forms docking domains
The phosphorylase-tyrosine together with surrounding amino acids are recognised by SH2 domains of other proteins allowing them to bind and undergo activation
How do tyrosine kinase receptors cause a reaction?
1.Auto-phosphorylation takes place at a no. of sites of the tyrosine kinase
2.These sites, some, are recognised by other proteins
Grb-2 will undergo a conformational change which will then allow it to interact with another protein called GEF (stands for guanine-nucleotide exchange factor)
This binding is happening through the SH2 domain
3.This will also cause a conformational change in GEF which will allow it to interact with and activate Ras
Ras is a membrane-associated protein
In its inactive state has GDP bound to it
4.Upon activation the GDP will be expelled and exchanged for GTP
5. This Ras GTP is activated and can go on to activate a no. of intracellular pathways
Another particularly important protein is PI3-kinase
6.This too recognises and interacts with specific residues on the activated tyrosine kinase receptor
7.This particular kinase will phosphorylate a membrane-associated lipid- PIP2
8.This will form PIP3
9.PIP3 will bind to and activate two proteins
The first is called PDK1 and the second is PKB
10.PDK1 will then phosphorylate and activate PKB (protein kinase B) which will then dissociate and go on to phosphorylate and activate other proteins within the signal transduction cascade
How do insulin receptors work?
The binding of insulin to the receptor causes the conformational change bringing the two subunits allowing auto-phosphorylation
IRS recognises and binds to the receptor through a SH2 domain
Recruitment of the receptor cause conformational change and activation and allows for the recruitment of other signal transduction proteins including IP3-kinase
In tissues that are responsive to insulin this can lead to a no. of physiological responses in the liver
In muscle this will lead to glycogen synthesis or stimulation of protein synthesis
It will also stimulate the expression of glucose transporters at the cell surface of some cells
This will increase glucose uptake
Insulin receptor substrate also recruits other proteins cut as Ras and Phospholipase C
How are phosphatase activated?
Kinases added phosphates
Phosphatase remove phosphates
1. As activation of these receptors leads to phosphorylation, dephosphorylation leads to inactivation
2. Phosphatases are activated as a result of receptor activation
3. Therefore the signalling process sets in motion events that leads to signal termination
PIEN is a phosphatase that dephosphorylates PIP3
How is Ras inactivated?
In the active form of Ras, the recruitment of other signalling proteins can be made, forming an active complex
In addition to the other responses of the Ras protein, it also contains activity known as GTPase activity
This will remove the phosphates and will inactivate the Ras
Under normal circumstances the kinetics of this are very slow
In order to enhance this regulatory reaction the Ras protein will interact with GTPase activating protein (GAP)
GAP binds to activated Ras and stimulates the GTPase activation within the protein
This leads to dissociation of the GTP and falling apart of the Ras complex
The dissociated Ras complex is recycled back to the inactive form of Ras
How do mutations in key regulatory mechanisms lead to cancer?
One of the processes that can be altered is the receptor expression
In some diseases, receptor expression increases
In others there is loss of phosphatase activity; removal of this activity, in this case, will lead to increased PDK1 activation
Other mutations have been found that will lead ti the loss of GTPase activity resulting in the fact that the Ras GTP is activated for longer periods of time
there is also loss of phosphatase activity that remove the phosphates from the receptor itself thereby inhibiting the inactivation process
Recall the Jak-STAT signalling pathway
- The growth hormone doesn’t have tyrosine kinase activity within itself so it has to interact with a protein called Jak which does posses tyrosine kinase activity
- Binding of a ligand to the growth hormone causes dimerisation followed by auto-phosphorylation; first of the Jak proteins which will lead to activation of Jak and then, following that activation, through phosphorylation of the receptor itself
- The phosphorylated receptor will then act as a docking site for a protein called STAT (signal transducer and activation of transcription)
- This will then form a dimer and will then dissociate and migrate to the nucleus where it will regulate gene expression of the target protein
How does a Smad-dependent signalling pathway occur (activated by TGF-beta)?
- This signalling pathway requires the expression of two different types of receptor; Type I and Type II
- They both have a serine-threonine kinase domain
- Activation of the Type II by binding of TGF-b leads to conformational change and it will dimerise with the Type I receptor
- The Type II receptor will then phosphorylate the Type I receptor and this phosphorylation will lead to the recruitment of molecules called Smad2 Smad3
- This will lead to phosphorylation of Smad which will then dissociate from the receptor and dimerise with Smad4
- This dimer will then translocate to the nucleus where it will regulate gene expression
What are intracellular receptors?
Receptors activated by molecules that readily pass across the plasma membrane and are largely insoluble in aqueous environments e.g. thyroid hormones and steroid hormones etc.
How does a steroid hormone work?
The receptor is actually a cytosolic receptor bound to a heat shock protein
The binding of the cortisol to this complex results in two things happening:
1. Is the dissociation of the heat shock protein
2. The glucocorticoid receptor with the glucocorticoid bound will form a dimer
This dimer will then migrate into the nucleus where it will bind to a glucocorticoid response element
This binding will lead to an increase in gene transcription
How does a thyroid hormone receptor work?
T3, the thyroid hormone, will be delivered to the cell bound to a binding globulin
It will then diffuse across the plasma membrane into the nucleus where it will then bind to the thyroid hormone receptor
Through activation of a number of other associated proteins, which form the thyroid response element will lead to gene transcription
