The next receptor I want to talk about is a special form of the
human epidermal growth factor receptor called the HER2 receptor.
Now, this receptor has mutation effects that affect
its gene expression, not the actual protein itself.
I need to tell you first a
little bit about the receptor.
Now HER2 is an unusual form of the
epidermal growth factor receptor;
there are many different epidermal growth factor receptors.
Normally HER2 does not require EGF binding for dimerization
and activation, meaning that two different monomer HER2
receptors, if they find each other can activate each other
without EGF and cause the process of cell division to occur.
Since HER2 is made at a very low level inside of
cells, this normally isn’t a problem because it’s
rare that the two individual monomers find each
other to activate the process of cell division.
So, however, there are mutations that happen
to the control region for the expression
of HER2, that if they happen will cause
HER2 to be made in large quantities.
Well when this happens, HER2
finds itself all the time.
And since when it finds itself, and
doesn’t require EGF, every time it
finds a partner, it’s going to stimulate
the process of cell division.
That means that mutations that increase
the quantity of HER2 are problematic.
Now, mutations that increase the levels of
HER2 are found in several types of cancer.
It’s found actually in
15-30% of breast cancers.
It’s found commonly in ovarian cancer,
stomach cancer and also in uterine cancer.
Now, fortunately this type of cancer
is actually fairly easy to treat.
It’s treated with a monoclonal
antibody known as herceptin.
And this treatment has revolutionized the treatment
of cancers that affect HER2, because it has
very few side effects and the way that it works,
it binds to HER2 and prevents it from dimerizing.
So if a person has that mutation that
makes too much HER2, treatment with
herceptin will stop that signal from
telling the cells to continue to divide.
The last system I want to talk about involving receptors
and tyrosine kinases is that of the Bcr-Abl system.
So the Bcr-Abl system is an oncogene that occurs as a
result of crossover between two different human chromosomes
that brings together the region of two different proteins
that didn’t start out that way in the first place.
The two different proteins
are known as Bcr and Abl.
So in the normal scheme of things, Bcr is found
on chromosome 22 and Abl is found on chromosome 9.
This crossover that occurs as you
can see on the screen is known as
the Philadelphia crossover and
causes Bcr to become fused to Abl.
Now this has some very
In this process, the control region of Bcr is fused to that
of Abl, and part of the coding of Bcr is also fused to Abl.
Well normally, Abl is expressed
at a fairly low level in the cell.
What is Abl?
Well Abl is a tyrosine kinase that participates in this
signaling process that we’ve talked about several times now.
Again, at a fairly low level, Abl
is participating in the signaling
and causing cell division to happen at a relatively low level.
The fusion of Bcr to it however,
causes this fusion protein, the
Bcr-Abl fusion to be made in much higher quantities than before.
And this has the effect of increase in the amount of
tyrosine kinase, of Abl being able to communicate signal.
And just like we saw with the HER2, an increase in that
signal now causes the cell to divide uncontrollably.
Well again fortunately, our knowledge about the molecular
biology and the structure of these proteins has enabled
some treatments to be developed that has also helped to
revolutionize people who have these types of cancers.
The treatment of people who have Bcr-Abl cancers
with tyrosine kinase inhibitors has been
very effective in reducing the effects of this
overall crossover that we described here.
Now this crossover happens in people who
have chronic myeloid leukemia or CML.
Treatment of these people with the
tyrosine kinase inhibitors has drastically
reduced the incidence of the cancer and
extended the lifetimes of many people.
Now the Bcr-Abl fusion occurs in about 90% of the
people who have chronic myelogenous leukemia.
That’s a pretty high percentage.
The way that this cancer is treated is by using
a tyrosine kinase inhibitor known as Gleevec.
Gleevec the structure is
shown on the right here.
Gleevec has almost doubled the five year
survival rate of CML patients; a remarkable
drug that happened as a result of our knowledge
about how tyrosine kinases actually work.
Well in this lecture I’ve spent a
lot of time talking about receptors.
From the receptors that control enzymatic functions, that
work very rapidly, to receptor protein receptors that
affect gene expression to internal nuclear affecting
receptors that control the overall expression of genes.