Lecture notes
RAS and MAPK
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- Aston University, Birmingham (Aston)
In depth cell signalling and physiology notes, created using synchronous and asynchronous material.
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RAS/MAPK signalling Second phosphorylation cascade that is activated in response to RTK stimulation and
that cascade is the RAS/MAPK pathway.
Signal transduction via Ras/MAPK pathway
We are still looking at signalling through tyrosine kinase receptors.
The Ras GTPase
The Ras protein is a small GTPase.
GTPases are enzymes that bind to the nucleotide guanine triphosphate (GTP) and
hydrolyse it to guanine triphosphate (GDP).
Ras is constantly cycling between an active GTP bound form and an inactive GDP
bound form.
This cycling is promoted through the activity of other proteins, these include guanine
nucleotide exchange factor (GEF), which promote the activation of Ras and GTPase
activating proteins (GAP), which promote the conversion of Ras-GTP to GDP.
Signal transduction: RAS/MAPK
In the context of insulin signalling and the activation of the insulin receptor tyrosine
kinase, the initial signalling events are the same as we’ve seen before.
The insulin ligand will bind to the receptor, and this induces the receptor to change
shape, this leads to the autophosphorylation of specific tyrosine residues within the
cytoplasmic tails of the receptor.
Those phosphorylated tyrosine residues will recruit the IRS proteins through the SH2
domains within the IRS proteins.
Recruitment of IRS to the activated receptor leads to their phosphorylation.
Once the IRS proteins are phosphorylated can then act as adaptor proteins. In the
context of RAS/MAPK kinase signalling they will bind to a second class of adaptor
proteins, called Grb2.
Grb2 has no intrinsic activity, but it acts as a protein interactor bringing other
proteins up to the signalling complex that is forming at the intracellular sight of the
activated receptor.
For RAS/MAPK signalling the protein binding partner for Grb2 is SOS, this is because
SOS functions as a RAS gef. So it is going to promote the conversion of inactive RAS
GDP to active RAS GTP.
Once activated RAS can then initiate a phosphorylation cascade, through the
sequential activation of a series of other kinases.
Ras will phosphorylate and activate Raf kinase, which will in turn phosphorylate and
activate Mek kinase, which will in turn phosphorylate and activate Erk kinase.
These phosphorylation cascades allow for the amplification of that initial signalling
ligand.
In this branch of the insulin receptor tyrosine kinase signal transduction pathway,
activated ErK, functions as our downstream effector of signalling.
Activated ERK mediates cellular changes.
Activated ERK is responsible for a lot of cellular changes in response to signalling
activation, this is because it has over 200 cellular targets.
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