Next I’d like to talk about another very
interesting set of receptor proteins.
These are known as the receptor tyrosine
kinase proteins and they’re involved in very
important signaling that help to control the
cell’s decision to divide or not to divide.
Now, receptor tyrosine kinases or
RTKs are also membrane bound proteins.
And these are also kinases.
That means that they put
phosphates onto other proteins.
But unlike protein kinase A which puts
phosphates onto serines and threonines,
RTKs put phosphates onto the side
chains of tyrosines of target proteins.
And it turns out that phosphorylation
of tyrosines gives a very different
kind of a signal than phosphorylation of serines and threonines.
We can see the phosphorylation of tyrosine happening
as a result of catalysis by RTK in this process
right here, and they’re simply the addition of
a phosphate to the hydroxyl group of tyrosine.
RTKs play very important roles as I said in
regulating whether or not cells are going to divide.
Now RTKs usually work as
a result of dimerization.
What does that mean?
Well RTKs are found in cell membranes as
individual units; an RTK here and an RTK over here.
Each of those individual units as they exist will
be inactive, but the binding of a hormone causes
the two subunits, or the two units of the protein
to actually come together into one, that’s a dimer.
That dimer is then active.
So the activation of an RTK happens by the binding of the
hormone that causes dimerization of individual subunits.
We see schematically here, two RTKs, individual
subunits embedded in a lipid bilayer.
There’s the lipid bilayer.
And we see the outside of the cell is at the top
and the inside of the cell is to the bottom.
The RTK monomers have a
binding site for the hormone.
They also have what’s known as a
transmembrane α-helix, and that’s just
simply a part of the protein that
projects through that lipid bilayer.
Like the seven TM I described before,
they have a part that is outside,
that grabs the message, and a part
inside that communicates the message.
It’s the cytoplasmic domain of the tyrosine protein
kinase that becomes activated on dimerization.
And when it’s in the monomeric form,
it’s inactive as you see here.
Well here’s the activation process.
We see the binding of a
hormone occurring here.
And the binding of the hormone actually
causes the two units to come together.
The bottom portion of these protein subunits as
I’ve shown here are actually tyrosine kinases.
And now they’ve been activated by being
brought into close proximity of each other.
These tails of these individual
RTKs phosphorylate each other.
One phosphorylating the other, which in turn causes each
of them to become much more active than they were before.
Those RTKs are active and
they can do one of two things.
They can either put phosphates on other
proteins that are inside the cell or the fact
that they have phosphates on them becomes a
target for binding of other proteins to them.
We’ll see that happen here.
In any event, what we’ve created as a result of binding of the
hormone is with activated of the tyrosine kinase of these RTKs.
So, one of the things that can happen as I said is the binding
of other proteins to these phosphates that are on there.
The binding of other proteins is mediated through a
special binding part of proteins called an SH2 domain.
SH2 domains recognize phosphotyrosines
and grab a hold of them.
And we can see that actually happening here in
formation of what’s called a signaling complex.
The signaling complex has multiple protein subunits which
I’ve drawn with some oval and triangles and a star.
And this signaling complex will help
communicate that message into the cell.
Now, looking at what’s been happening here, we see the
binding of the hormone to the RTK in the membrane.
The receptor dimerizes, there’s an
autophosphorylation that happens.
And by the way, these happen in all
of the RTKs that I’ll describe.
As their signaling complex
that becomes assembled.
And now the message is
communicated into the cell.
So here’s one RTK known
as the insulin receptor.
The insulin receptor as its name suggests is a
protein in the membrane that binds to insulin.
And on the inside it has
the tyrosine kinase.
And that tyrosine kinase allows
it to phosphorylate things.
Now insulin receptor is actually a little
unusual in that it doesn’t start as a monomer.
It’s one of the few RTKs that
actually start as a dimer.
The two units are already
held in close proximity.
But they don’t become active
until they bind to the insulin.
It’s the binding of the insulin that
causes them to become activated.
But the activation doesn’t require them to
come together, they’re already together.
So here’s this process that happens with
the insulin RTK - autophosphorylation.
And now we see the beginning
of the signaling complex.
The signaling complex starts with the
binding of a protein called IRS-1.
And IRS-1 has multiple
things that it can do.
It can interact with other signaling
pathways as you see in the arrow going
upwards, or in the case of the insulin
pathway, that is the response of insulin.
What it does, is it activates
another kinase known as PI3.
PI3 catalyzes the formation
of a molecule called PIP3.
PIP3 is a second messenger.
It’s a small molecule, meaning it’s not a protein
and it’s helping to communicate that message.
PIP3 interacts with a protein called PDK1,
which is another kinase and activates it.
Well finally, activation of Akt kinase causes
another protein to move to the cell surface.
This other protein is known as GLUT4.
What is GLUT4?
GLUT4 stands for glucose
transport protein 4.
What does GLUT4 do?
Well when it moves to the cell membrane,
it embeds itself in the membrane.
And the function of GLUT4 is to pull
glucose out of the extracellular part
of the cell into the cell, and have
the glucose available for the cell.
That’s important because that’s
ultimately what insulin is trying to do.
Our body makes insulin after we have a
meal, and our blood glucose levels rise.
Blood glucose is actually
hazardous for the body.
To reduce the blood glucose level, insulin
binds to a receptor and stimulates the cells
to take up that glucose, thereby reducing
the level of glucose in our bloodstream.
So this overall process which
had many steps, had one aim.
And that one aim was to get
the cells to take up glucose.
Well in addition to causing glucose
to come into the cell, one of
the things that the cell has to do is to deal with that glucose.
Well glucose is actually what I
describe as a poison for a cell.
That means too much of it
really causes a problem.
So the cell doesn’t want to have too much
free glucose sitting around inside of itself.
How does it deal with
that extra glucose?
Well if you remember back to the
pathway that I showed you for the
glycogen breakdown and glycogen
synthesis, I showed that phosphoprotein
phosphatase was involved in that last step that inactivated the
breakdown of glycogen and activated the synthesis of glycogen.
That phosphoprotein phosphatase is turning off
glycogen breakdown and turning on glycogen synthesis.
What does it take for
So that glucose that’s coming into the cell is built
into glycogen, and glycogen is not a poison for the cell.
A pretty cool process.
Now, insulin signaling happens in a
reciprocal fashion to epinephrine signaling.
And I want to show you
that in this slide.
The β-adrenergic receptor pathway,
which was the pathway that activated
the breakdown of glycogen, operates
in the manner that you see here.
And I won’t go through all
the individual steps.
The net upshot of that is that glycogen is
broken down and blood glucose levels rise.
This is good if somebody’s chasing you because
you want the energy to be able to run away.
After you’ve had a meal however,
you’ll want to deal with that glucose.
That involves the insulin receptor
pathway which does a couple of things.
One, is it’s moving that GLUT to
the membrane so that the membrane-- that
the glucose can now move across the membrane and into the cell.
And phosphoprotein phosphatase
is activated so that the glycogen
breakdown can stop and the glycogen synthesis can start.
As a result of insulin action, glycogen
is made and blood glucose levels fall.
These processes are happening in exactly the opposite fashion
in the reciprocal regulation that I’ve describe before.