Receptor Mechanism III Flashcards
What are the three growth receptors discussed, and what are some examples of each?
TYROSINE RECEPTORS KINASE:
- Insulin
- Epidermal Growth Factor (EGF)
- Platlet-Derived Growth Factor (PDGF)
JAK/STAT:
- Growth Hormone
- Interferon
SERINE THREONINE RECEPTOR KINASE:
- TGF-β
What are enzyme linked receptors involved in?
They are involved in the regulation of:
- Cell growth
- Division
- Differentiation
- Survival
- Migration
Inappropriate activation, or a mutation in either the enzyme or the receptor is associated with disease, particularly cancer.
What do we mean by tyrosine kinase activity?
Dimerisation brings two receptor molecules together, allowing for the phosphorylation of specific tyrosine residues.
Not all tyrosine residues can be phosphorylated.
The phosphotyrosine together with surrounding amino acids are recognised by SH2 domains of other proteins, allowing them to bind and undergo activation.
Describe how the activation of tyrosine kinase receptors activates multiple pathways.
The phosphorylated tyrosine acts as a docking site for SH2 domains on other proteins.
An example of such a protein is Grb-2, an adaptor protein. When Grb-2 docks on the phosphorylated tyrosine, another protein, Ras GEF, binds to Grb-2.
This Ras GEF facilitates the exchange of GDP for GTP in Ras proteins. The now activated Ras initiates a number of different signals. Ras is an important molecule in the regulation of cellular activation and growth. Mutations in Ras are common in many tumours.
Another example of a protein that docks on phosphorylated tyrosine is PI 3-Kinase. The activated PI 3-Kinase phosphorylated PIP2 to PIP3. This allows for the activation of PDK1, which kleads to the activation of PKB. When activated, the PKB dissociates from the PIP3.
The activated, dissociated PKB can be used in protein synthesis and glycogen synthesis, and in the movement of receptor vesicles for glucose uptake.
Describe insulin receptors.
They act on the liver and muslce to reduce blood glucose.
It consists of 2 α and 2 β subunits linked by disulphide bridges. It also has tyrosine kinase activity.
Describe the activation of insulin receptors.
When insulin binds to the receptor, autophosphorylation of the 2 β chains occurs. An Insulin Receptor Substrate (IRS) docks on the phosphorylated tyrosine, which in turn activates PI 3-Kinase, which then continues to go down that pathway.
How are receptor kinases inactivated?
As activation of these receptors leads to phosphorylation, de-phosphorylation leads to inactivation.
Phosphatases are activated as a result of the receptor activation. Therefore the signalling process sets in motion events that lead to signal termination
In addition to that:
- small G-proteins have intrinsic GTPase activity.
- receptor internalisation occurs: this is when we remove receptors from the surface of the membrane.
Describe the Ras molecule.
Ras is one of a number of small G-proteins. It’s related to the Gα subunit of cAMP. It is inactive GDP bound.
When active, is replaced by GTP, helped by Guanine nucleotide exchange factor (GEF)
It’s involved in growth, differentiation cell motility etc.
It contains GTPase activity, slow de-phosphorylation helped by GTPase-activating proteins (GAP).
Mutated Ras is found in 30% of human tumours.
How is the activity of Ras regulated?
When it is GDP-bound, the Ras molecule is inactivate. With the help of GEF (Guanine-nucleotide Exchange Factor), the GDP is replaced for a GTP molecule. With Raf now binding to the Ras molecule, it is now active.
When it needs to be inactivated, GAP (GTPase Activating Protein) assists in the dephosphorylation of GTP to GDP. This means that the RAF now dissociates from the Ras molecule, and it is now rendered inactive.
What are some mutations in key regulatory mechanisms that can lead to cancer?
- overexpression of EGF receptors on some breast cancers
- loss of GTPase activity
- loss of phosphatase activity
Describe the JAK/STAT signalling pathway.
This pathway is activated by growth hormone.
When the receptors bind, they dimerise. Then, the JAKs on them cross-phosphorylate, then phosphorylate the receptors.
These phosphorylated tyrosines now act as docking sites for STATs. When the STATs dock, the JAKs phosphorylate them. Then, the STATs dissociate from the receptor and dimerise via the SH2 domain.
They then enter the nucleus, bind with gene regulatory proteins, act on the target gene and start transcription.
Describe the Smad-dependant signalling pathway.
This pathway is activated by TGF-β.
TGF-β binds to a Type II TGF-β receptor. This binding allows the association of the Type I TGF-β receptor with the Type II TGF-β receptor, and in response to that, the serine/threonine kinase domain on the Type II receptor phosphorylates the Type I TGF-β receptor.
The Type I receptor activates Smad 2 or Smad 3 molecules. This allows them to interact with a subsequent Smad molecule called Smad 4. Then, as a heterodimer, they will then be translocated into the nucleus, bind with gene regulatory proteins, act on the TGF-β target gene and start transcription.
