The next receptor system I’d like to talk about is that
of the epidermal growth factor receptor or the EGFR.
Like the other receptors I’ve been talking about, the epidermal
growth factor receptor is a receptor tyrosine kinase.
It dimerizes on binding to
epidermal growth factor or EGF.
Now EGF is a protein that’s involved in
the growth and proliferation of cells.
And EGF helps to control
that overall process.
So let’s take a look at the
signaling pathway up close.
We see on this figure, the binding of EGF shown in green,
on the outside part of the cell to the EGF receptor.
The receptor here has dimerized and is
holding that EGF in the cell membrane.
We can see some accessory proteins
that have come along and have
started to form the signaling complex on the inside of the cell.
This includes a protein known as GRB2.
And GRB2 is binding to phosphoytyrosines that are on
the cytoplasmic side of the cell, on the EGF receptor.
That autophosphorylation that I
described before has happened here.
And this GRB2 has an SH2 domain that recognizes
those phosphoproteins and binds to them.
GRB2 binds to another protein known as SOS,
which for our purposes here is insignificant.
But what is significant is the next
protein that binds which is known as RAS.
Now RAS is a protein that’s very intimately involved
in controlling the cell’s decision to divide.
RAS is a protein that is very much like the G-protein
that I described before in the beta-adrenergic receptor.
It’s of similar size and it also
binds to guanine nucleotides.
The guanine nucleotide that
it binds to here is GDP.
And when it gets activated, which
is what’s happening in this process,
the GDP is replaced by GTP and RAS
is now active to go do its thing.
And active RAS prepares
a cell for division.
Well there’s still more to this pathway; RAS in turn goes to
another protein known as RAF which is a kinase and activates it.
RAF puts a phosphate onto another protein known as MEK,
which is a kinase which puts a phosphate onto another
protein known as MAPK, which is of course a kinase that
puts phosphates onto other proteins as we can see here.
Now, the order of this for our
purposes isn’t significant.
What’s important though is what’s
happening in the overall process.
This cascade of phosphorylations that’s happening
is causing a bunch of different proteins to become
active, and it’s affecting at the very bottom, some
proteins that are known as transcription factors.
These transcription factors become
activated by the addition of the phosphate.
And they move into the cell nucleus as you
can see here to co-activate gene expression.
The genes that they’re activating
will stimulate the cell to divide.
So epidermal growth factor has
favored the process of cell division.
Well before I go further I need to
say an interesting word about RAS.
RAS is actually a family of related proteins,
it’s not just one, there are actually several.
Each of these proteins is monomeric, that
differs from what we saw with the G-proteins
before; they had the heterotrimers that we had
associated with the β-adrenergic receptor.
RAS proteins can bind guanine
nucleotides as we saw.
And this human RAS that’s
shown here is bound to a GDP.
RAS swaps GDP for GTP when it gets activated by
that signaling complex that I showed earlier.
Now like the α subunit of the β-adrenergic
receptor, RAS is also a bad enzyme.
It very slowly cleaves GTP to GDP, meaning
that RAS turns itself off over time.
Well that’s good, because you don’t
want a cell continually turned
on and continually dividing because
that becomes known as a cancer.
What we said before was important for a cell to be able to turn
off a signal just like it was important to turn on a signal.
And that’s particularly important
for RAS as we have seen.
Now RAS as I said, is a bad GTPase.
It converts GTP into GDP
and turns itself off.
What happens if RAS
can’t turn itself off?
That happens sometimes.
And it happens too
They are what are called point mutations or
single base changes within the RAS coding
sequences that if they change, they can
affect the ability of RAS to cleave GTP.
If they inhibit RAS’s ability to cleave
GTP, RAS is always left in the on state.
Well, you saw from the last slide what happens
if it’s left in the on state continuously,
the cell will continue to divide
uncontrollably and that can lead to cancer.
And RAS is implicated in
numerous human cancers.
Now other things need to
be turned off as well.
The RTK that was the EGF receptor that I talked
about specifically here also has to be turned off.
How does it get turned off?
Well, like the β-adrenergic receptor, it
gets internalized into the cell in a process
known as endocytosis, thus removing it from
being part of the signaling processes.
The phosphatases that get stimulated
in the schemes that I’ve shown
before are proteins that remove phosphates from other proteins.
And this whole cascade that I showed before, there
was a whole series of phosphorylated proteins.
A phosphoprotein phosphatase acting on them
inactivates the entire pathway with a single action.
That’s pretty cool.
Now you might wonder, how is it that phosphoprotein
phosphatase itself gets inactivated?
And it turns out that it gets inactivated
by an interesting phosphorylation process.
I wanted to take a
minute and show you that.
On the right part of the screen you
can see the phosphoprotein phosphatase
that’s in green, that is bound to a protein
called Gm; that’s not a G-protein.
It’s just a muscle protein called Gm.
In the form that you see
on the top, it’s active.
But a phosphorylation of the Gm, causes the
Gm to release the phosphoprotein phosphatase.
That leaves the phosphoprotein
phosphatase less active.
You also see floating
out there, an inhibitor.
The inhibitor by itself doesn’t bind to the
phosphoprotein phosphatase and inhibit it.
Rather what it does, is it waits for the
inhibitor to get itself phosphorylated.
When the inhibitor gets phosphorylated, phosphoprotein
phosphatase binds to it and is then completely inactivated.
So that’s how it gets inactivated.
The question then is, when
does it get inactivated?
And it gets inactivated by
action of protein kinase A.
Now think about this
This reciprocal regulation is causing one set
of enzymes to become active on binding of
one hormone, and another to become inactive,
and then flip them with the other hormone.
So in the case of epinephrine for
example that I talked about, it was
stimulating proteins that were
important in breaking down glycogen.
And insulin was important for stimulating
proteins that were making glycogen.
We see that that reciprocal regulation extends all the way
down to turning off proteins like phosphoprotein phosphatase.
Pretty cool process.