EGFR – one protein’s story
EGF (epidermal growth factor) and its receptor are special to Vanderbilt University. Stanley Cohen, Ph.D., now an emeritus professor of Biochemistry, was awarded the Nobel Prize in 1986 for his discovery of EGF and its role in cell growth. Cohen and colleagues were the first to characterize the EGF receptor and describe its fundamental features.
EGF and its receptor are now known to be members of a large family of proteins, all involved together in the complex regulation of cell growth. These family members are targets for drugs designed to block the abnormal growth characteristics of cancer cells.
We all start out the same way—being pieced together like so many beaded necklaces—according to the plans. And yet, even though
we come off the same assembly lines, we are not at all the same.The plans instruct some of us to act like two-by-fours, supporting the walls. They direct others
of us to act as couriers, or janitors, or assembly line workers. Others still get sent out, to
work in the larger world.
Our world is a single cell. We are proteins.
You can think of our world, the cell, as a sort of factory—a very tiny factory, and only one among the millions
that make up the human body. It is a place busy with manufacturing. We are the factory’s products and its staff. So really, we manufacture ourselves. But
without the plans.
Here’s how it works. The plans—the DNA blueprints—are stored in a central office, the nucleus, where they are cared for, you might even say coddled, by proteins. The proteins in the nucleus fancy themselves as having the most important jobs. They rush in to patch tiny tears in the blueprints. Or they copy parts of the plans to send to the assembly lines for the production of new proteins. Or they coat the DNA and keep it safe during storage. They do keep things humming in the central office, but still I’d rather have my job—at the factory wall.
I am a receptor, specifically an EGF receptor. I spend my time at the cell surface, part of me poking out of the cell, part poking in. Kind of
like the doorman who greets Dorothy and her friends at the Emerald City with his head and upper body sticking out the door, the rest safely
inside. I will tell you about what I do at the cell surface, but first I want to give you a little background on how I got here.
Like the rest of the proteins
in the cell, I was put together on one of the assembly lines. Earlier, I referred to us proteins as being like beaded necklaces. Here’s why. We are made
of chemical “beads” called amino acids. Twenty different kinds of amino acid beads are strung
together in a particular order for each protein, based on a copy of the plans. So the blueprints might say something like: purple, green, green, blue, red, yellow, purple, yellow, blue …, really the DNA spells out the order of the amino acids, not colors of beads, but you get the idea. The
assembly line proteins read out the order, pick out the right amino acids, and put them together in long protein strings.
The order of the beads, then, makes each of us unique. The order determines what we do and the shapes that we take. At the end of the manufacturing process, we don’t end up with our amino acids all in a tidy straight line. Instead, we coil and twist as we are made—with the help of folding proteins, until we look like hopelessly tangled necklaces. Scientists call this our structure. Though it may look like a globby mess, the bumps and dips in our structures are carefully constructed for the interactions we have with other proteins and molecules inside and outside the cell.
After we come off the assembly line, we load into a series of shuttles for transport to our
job sites in the cell. En route, we can receive some additional decorations—flourishes added to some of our beads—like you might put on a scarf, or
a hat. Our decorations are things like
sugars and fatty acid chains; they outfit us for our jobs. Because of varying accessories, even two EGF receptors might end up looking a little bit different from each other. We proteins, you see, are as individual as are you human beings.
So I made it
out to the cell surface, along with a shuttle full of other proteins bound for the same destination. As I told you, I am a receptor, which means my job is
to receive incoming messages. Well, only certain arriving messages. I am specialized to respond to epidermal
growth factor (EGF) and a handful of other signals that are similar to EGF.
EGF—itself a protein, by the way—is one of the many messenger molecules that continuously bombard
the outside of the cell. A few of these signal molecules can pass directly through the membrane, but most must interact with a receptor to have their message
Hundreds of different receptors, as well as other kinds of proteins, stud the cell surface. I am not the lone receiver of EGF signals—other EGF receptors and our family members join me in the task. Our family members actually work as pairs to send messages inside the cell.
When EGF sticks to us and we team up, we pass the signal along to a host of proteins inside the cell. These courier proteins are waiting nearby, just inside the walls, ready to take the message from us and speed off, transmitting it to parts deep inside the factory.
The courier proteins know that a pair of us has received a message because we perform a chemical reaction, called phosphorylation, on ourselves. We take a kind of sticker—a phosphate group—from a molecule called ATP and stick it onto some of our amino acid beads. These phosphate stickers are signals for the courier proteins to interact with us so we can tell them the message. They then share the information with still other proteins, and eventually the message can make it all the way to the central office, the nucleus, where the DNA is stored.
The messages that make their way to the nucleus affect which plans are copied for the assembly of new proteins. This is how messages from outside the cell alter the types of proteins being manufactured inside the cell.
from my receptor family will send the cell into a growth mode; the cell will duplicate its DNA and split itself into two cells. With continued growth signals,
these two cells can split again, making four, and so on. It doesn’t take long to have a bunch of new cells. This
is good if you’re trying to make a new organ, or replace damaged tissue. It’s bad if the cells are dividing for no healthy reason, like tumor cells do.
to say that my family members and I participate in processes that can turn normal cells into tumor cells. It happens when things go awry—the plans get
changed—and the assembly lines churn out way too many of us. Or we’re made a little differently so that we’re
able to send signals all the time, not just in response to EGF.
In situations like these, there are new drugs that aim to keep us in check. Some of these medicines work by jamming up the place where EGF sticks to us. Some, like a new one called Iressa, bind our hands, in a sense, making us unable to put the phosphate “stickers” on ourselves or on other proteins. These drugs may help, but tumor cells are a tricky lot; they’re good at figuring out ways to get around such roadblocks.
As for me, I’m nearing the end of my shift. I’ve put in a good day’s work here at the factory wall, and I’m spent. The cell will replace me with a brand new EGF receptor. And I will board a shuttle bound for the lysosome—our cellular recycling center. There, I will be dismantled so that my amino acid beads can be reused to manufacture some other protein. I’m hoping they don’t end up being used to make one of those central office types!