Interplay between growth factor receptor trafficking and signalling
Learning objective
1. C-Met signals from the endosome
2. C-Met signalling on endosome promotes tumorigenesis
3. The endosome: a signalling platform
Explain 2 reasons why a receptor signals on endosome rather than only on plasma membrane, which are the following:
4. Signalling en endosome: protection against phosphatases
5. Signalling en endosome: access to specific signals
c-Met/HGF
Example used is c-Met and will always hear about c-Met
Text book shows C-Met receptor found at the plasma membrane or surface of the cell and ligand binds to receptor
The binding of ligand will trigger c-Met activation and signalling, which occurs at the plasma membrane as shown in
the image.
Receptor compartmental signalling
Another consequence of ligand binding is internalisation of receptor (RTK), which occurs in sec/min (rapid).
Endocytosis and signalling mechanism are complex and scientist do not completely understand or know which occurs
first but may require each other.
The receptor does not only signal at the plasma membrane but also inside the cell in endosome
There is literature showing that signalling also occurs on the ER and not always on the endosome. In this module, will
only speak about signalling in endosome.
The receptor enters cell while still being bound to its ligand however this is not shown in the image.
- Red oval= receptor
- Red circle = ligand
In the endosome, the ligand bound active receptor can still be associated to signalling molecules and adaptors
There are not many pathways known to be activated on structures, such as endosome. Therefore, this is just the
beginning.
So far only believe that the signalling cascade occurs at the PM but the same signalling cascade may be occurring on
organelles/compartments.
The following can be a possibility, currently there is no consensus but both could happen
- It may be that some of the signalling starts at the plasma membrane and once the receptor enters the cell the
signalling is sustained on the receptor
- Some signalling pathways may only occur on the endosome
, l- c-Met signals from the endosome
Once the receptor enters the cell it will go into the early endosome followed by late endosome and the get degraded
ERK is a protein in the MAPK/ERK pathway (also known as ras-raf-MEK-ERK pathway) is a chain of proteins in the cell
that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus
Image showing c-Met receptor at the plasma membrane, the ligand, HGF binds to c-Met and enters the early
endosome and traffics along microtubules to the late endosome.
ERK (protein) gets phosphorylated
ETK can signal on an endosome
Internalisation of the c-Met receptor
- Once the receptor enters the cell, the receptor goes on the early endosome followed by MVB/late endosome
and then degraded.
- This is still true as after 2 hours, 50% of the c-Met has been degraded and the other 50% is still inside the cell
- The remaining 50% c-Met receptor may have been recycled back to the PM
Most of receptor tyrosine kinases get endocytosed and then degraded. In certain situation, RTK gets recycled but
usually endocytosis pathway is preferred.
Between the time the receptor gets in the cell and degrades, the receptor is bound to ligand and signalling molecules
and can activate signalling pathways.
Learning objective
1. C-Met signals from the endosome
2. C-Met signalling on endosome promotes tumorigenesis
3. The endosome: a signalling platform
Explain 2 reasons why a receptor signals on endosome rather than only on plasma membrane, which are the following:
4. Signalling en endosome: protection against phosphatases
5. Signalling en endosome: access to specific signals
c-Met/HGF
Example used is c-Met and will always hear about c-Met
Text book shows C-Met receptor found at the plasma membrane or surface of the cell and ligand binds to receptor
The binding of ligand will trigger c-Met activation and signalling, which occurs at the plasma membrane as shown in
the image.
Receptor compartmental signalling
Another consequence of ligand binding is internalisation of receptor (RTK), which occurs in sec/min (rapid).
Endocytosis and signalling mechanism are complex and scientist do not completely understand or know which occurs
first but may require each other.
The receptor does not only signal at the plasma membrane but also inside the cell in endosome
There is literature showing that signalling also occurs on the ER and not always on the endosome. In this module, will
only speak about signalling in endosome.
The receptor enters cell while still being bound to its ligand however this is not shown in the image.
- Red oval= receptor
- Red circle = ligand
In the endosome, the ligand bound active receptor can still be associated to signalling molecules and adaptors
There are not many pathways known to be activated on structures, such as endosome. Therefore, this is just the
beginning.
So far only believe that the signalling cascade occurs at the PM but the same signalling cascade may be occurring on
organelles/compartments.
The following can be a possibility, currently there is no consensus but both could happen
- It may be that some of the signalling starts at the plasma membrane and once the receptor enters the cell the
signalling is sustained on the receptor
- Some signalling pathways may only occur on the endosome
, l- c-Met signals from the endosome
Once the receptor enters the cell it will go into the early endosome followed by late endosome and the get degraded
ERK is a protein in the MAPK/ERK pathway (also known as ras-raf-MEK-ERK pathway) is a chain of proteins in the cell
that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus
Image showing c-Met receptor at the plasma membrane, the ligand, HGF binds to c-Met and enters the early
endosome and traffics along microtubules to the late endosome.
ERK (protein) gets phosphorylated
ETK can signal on an endosome
Internalisation of the c-Met receptor
- Once the receptor enters the cell, the receptor goes on the early endosome followed by MVB/late endosome
and then degraded.
- This is still true as after 2 hours, 50% of the c-Met has been degraded and the other 50% is still inside the cell
- The remaining 50% c-Met receptor may have been recycled back to the PM
Most of receptor tyrosine kinases get endocytosed and then degraded. In certain situation, RTK gets recycled but
usually endocytosis pathway is preferred.
Between the time the receptor gets in the cell and degrades, the receptor is bound to ligand and signalling molecules
and can activate signalling pathways.
