When evolution first fashioned multicellular organisms, a problem arose. The main goal of unicellular organisms like bacteria and protozoans is to reproduce; to leave as many descendants as possible to ensure that their genes are passed to the next generation. While that aim continued with the advent of multicellularity, the individual cells in a multicellular creature are constrained. They are parts of a community and cannot go off, willy-nilly, reproducing on their own. Their ultimate job is to make sure that the genes carried by germ cells, sperm and eggs, not their own genes, are propagated. They live to sacrifice their own welfare for the greater good. As a part of this behavior, they must interact with their fellows, adjusting their rate of proliferation to match their neighbors so that tissues and organs form and function properly. Moreover, as cells die, new ones must replace them. That process too, tissue renewal, must be carefully controlled.
In order for organisms to regulate the growth of their tissues and organs, cells must communicate. They must inform each other when to divide, when to stop, even when to die. The major signalling molecules in this process are called "growth factors", and they generally are proteins. But proteins are much too large to cross cell membranes. How can a molecule like a protein affect the behavior of a cell if it can't pass through the cell membrane?
We've already seen the answer. Cells have proteins embedded in their membranes, called receptors, that function to pass information from outside to inside. How growth factors achieve this aim was first worked out by studying the mechanism of action of a growth factor, called EGF (for "epidermal growth factor"). EGF, as its name implies, serves to stimulate the proliferation of a variety of epidermal cells. It works by interacting with a receptor molecule, called logically enough, the EGF-receptor.
The figure above right shows the EGF-receptor protein before it has bound a molecule of growth factor. The yellow rectangle is supposed to represent a portion of the cell membrane. The receptor protein chain is shown as a dashed line. The portion of the receptor outside the cell is drawn in green and labelled "Binding Domain" (A domain is a portion of a protein that folds up independently of the rest, often performing a specific function. Domains will play a prominent role in future postings). EGF can affix to the binding domain. A small area of the protein, drawn in red, traverses the membrane (the "Transmembrane Domain"). A third section of the receptor that lies inside the cell is called the "Kinase Domain". It is shown as a blue bulge. Its function is to enzymatically transfer phosphate groups from ATP or GTP to another protein. Below the kinase domain is a tail of amino acids, that is located at the terminus of the protein.
As mentioned in a previous post in conjunction with immune receptors, the EGF receptor is free to move laterally within the membrane. Occasionally, it contacts another similar receptor and briefly forms a dimer (see the second illustration at the right and compare it with the one above). As shown, these transient dimers are good at binding EGF. When EGF binds it both stabilizes the association between the two receptors and activates the two closely opposed kinase domains. They add phosphate groups onto specific amino acids (tyrosines) in the tails of their adjoining partners. We'll delve into the consequences of this transphosphorylation in the next post, but suffice it to say, they are profound, allowing the receptor to set up a cascade of reactions that promote cell growth.
There are many growth factors that interact with their specific receptors and operate in a manner similar to the EGF receptor. Weinberg claims that DNA sequencing of the human genome has identified 59 proteins that bear close resemblance and presumably have similar functions. If that isn't enough, there are a host of other unrelated receptors that also send growth signals from the outside of cells to the inside. Some bear kinase domains and transfer phosphates to proteins, other use alternative mechanisms for signalling. A detailed description of these other receptors is beyond the scope of this blog. However, a key take home lesson is that many cancers harbor errors in receptors in general, errors that contribute to the malignancy of cells. I'll discuss this further in the upcoming posts.