The last thing I want to talk about in this lecture
relates to the process that I call signaling gone wild.
And we’ve already seen a little
bit of a hint of this already.
Signaling proteins play important roles in growth and division
as we’ve seen; the epidermal growth factor was a good example.
I need to define a term here that I’m going
to be using, so that you’re familiar with it.
And it’s a term you’ve probably heard
before, that term is oncogene.
An oncogene is a mutated form of a gene whose
activity can cause uncontrolled growth.
I’ve described one already,
that was the RAS protein.
When we mutated the cellular RAS protein so
that it could no longer cleave GTP, the RAS
protein was left in the on state and the cell
was left in a continual process of dividing.
That mutated RAS was an oncogene.
Well what was it before it mutated?
It was a normal gene we
call a proto-oncogene.
So a proto-oncogene is a gene that has the
ability to become an oncogene if it gets mutated.
And you start to think, well mutation
is one of the ways in which we can
make cancer, in fact mutation is the
primary way in which we can make cancer.
How do we avoid mutation?
Well there’s a variety of thoughts about that but one
of which is to be careful of the food you eat, the water
you drink and the air you breathe, because it’s materials
inside of those things that can cause and favor mutation.
Now mutations in signaling systems
can often lead to tumor formation.
They can happen in a variety of ways.
One way are those mutations that affect
the protein structure or function.
Let’s imagine that we had a receptor protein, let’s say the EGF
receptor protein that was left in the on state all the time.
If the receptor protein was always communicating a
signal to divide, that cell would become cancerous.
We could also have mutations that
affect the expression of a protein.
Mutations that affect the expression of a
protein may cause a protein that normally is
present at a very low level in the cell doing
very little to effect the signal to be
made in much larger quantities and now really
cause that signal to be heard like the kid
in the classroom whose hand is going up all
the time, “Teacher see me, see me, see me".
That protein that has that effect is now
causing the cell to divide, divide, divide.
So the level of expression can affect whether
or not a protein is an oncogene or not.
And there are other mutations that can happen that
may affect interactions with other proteins as well.
Well let’s look at a couple of examples,
I’ve already talked a little bit about RAS.
So GDP bound RAS we
learn, was inactive.
And that the GTP activated it.
The GTPase, because RAS is a very inefficient
enzyme normally converts GTP to GDP over time.
And so the signal gets turned off.
Now I pointed out that mutations in RAS can
cause RAS to cause that signal to always be on.
And there’s two sets of mutations that can
do that, that effect either amino acids 12
or 13, or amino acid 61; 12/13 depends on
the type of RAS that we’re talking about.
Each of these mutations prevents the RAS
from being able to turn off that signal.
Now what’s scary is, those are
single based mutations; one mutation.
You are one mutation away from
potentially having a tumor.
That’s kind of scary.
Activated RAS stimulates
So the more active RAS is, the more
likely you are to have that cancer.
I should also caution here that one
mutation does not make a tumor.
There’s actually a series of
events that can make a tumor.
Mutated RAS is the most common point
mutation we find in cancer because it’s
very simple to mutate RAS and have the
effects that I’ve described here.
Over 90% of pancreatic cancers
for example, have a mutated RAS.
And about 20% of all cancers that
are known can have a mutated RAS.
So RAS is very important
in that process.
Another example of signaling gone
wild is that of the SRC protein.
Now SRC protein is shown
on the screen here.
And it’s a tyrosine kinase but it’s
not a receptor tyrosine kinase.
It works internal to the cell.
It participates in that signaling
process that I described before.
So we saw a bunch of proteins that got
phosphorylated in the EGF signaling pathway.
So there are many kinases in the cell that
participate in the signaling process.
SRC proteins are-- participate in
a variety of signaling processes.
And they have the effect not of activating cell
division but actually of inactivating cell division.
So phosphorylation of SRC’s tyrosines doesn’t cause
it to be turned on, it causes SRC to be turned off.
That means that normally when the signaling process comes along
and it hits SRC, it’s telling the cell, “Don’t divide".
And SRC will stop that
cell from dividing.
Well what happens if SRC itself is mutated so
that those phosphates can’t be put onto it.
What happens is dephosphorylated SRC
will act to stimulate cell division.
So, you get it if you've got a phosphate on there,
you get it if you don’t have a phosphate on there.
You begin to get the idea that it’s
important to have the proper phosphate on at
the proper place, at the proper time, or
a cell is likely to become cancerous.
Mutations that affect any phosphorylation part of
SRC or enzymes that affect that SRC phosphorylation
will affect SRC’s ability to properly
communicate that signal and result in a cancer.
Now, there are proteins that activate
SRC by dephosphorylating it that
have also been detected at elevated
levels in various cancer cells.
So not only is the process of putting on
the phosphate important, but the removal
of that phosphate may also affect SRC’s
ability to properly communicate that signal.
Well I’ve said a fair amount then about the phosphorylation or
dephosphorylation of SRC and it’s
ability to affect the cell’s division.
So how does this overall
process actually work?
Well the phosphorylation of
tyrosines that are described in SRC
actually prevent the access of other
proteins to SRC’s SH2 domain.
That will prevent SRC from interacting with those proteins
because SH2 domains interact with phosphorylated tyrosines.
If the SH2 domain is covered up as it
is when the SRC is phosphorylated, then
SRC will not participate in the signaling
process that stimulates cell division.
Consequently, SRC is
therefore out of the picture.
Mutations that change the tyrosines leave the protein always
activated because there’s always access
to those-- the SH2 domains.