Signaling

Overview

:
Cell communication takes many forms, but there are commonalities in most of them. Cells may communicate by direct contacts between proteins on their surface, but do not need to be in physical contact for most events.
In general, there are three steps:
  1. A signal molecule, or “ligand,” usually soluble, floats up to the target cell. The signal molecule may be a small protein (such as insulin), or a much smaller molecule (such as “adrenaline,” usually known as “epinephrine”). It binds to the extracellular face of a receptor, a protein that spans the membrane of the target cell
  2. The receptor changes shape (conformation) when the ligand binds. This is no different in concept to the idea of allosteric changes to proteins we discussed when we talked about inhibitors or activators of enzymes. The tertiary structure of the protein changes. These changes affect not only the outside face of the receptor, but the internal side as well. This is the beginning of the “transduction” event. That’s how the information gets through the membrane.
  3. The change in shape on the inside of the receptor leads to some change in the biochemistry of the cell. It may make available a new binding site, or a new active site. But some change inside the cell happens. There is a nearly limitless set of possibilities. Frequently, some enzyme gets activated and makes something called a “second messenger.” This completes "transduction." In this way the signal is amplified and may have many effects. The second messenger may be cAMP, which we discussed, made from ATP by "adenyl cyclase." But, release of calcium from the smooth ER or other small molecules also could be involved.
  4. Ultimately, there are changes to how the cell behaves. This is the cellular response. It could include turning "on" or "off" certain genes, or changing the shape and/or migratory behavior of the cell. Or, it could send an "electrical" impulse down a long cell, as a nerve cell would.
  5. Eventually, the cell has to stop responding. The pathway has to have a way to shut down.

Signaling pathways are often called "cascades," because a single, initiating event can lead to wide ranging effects.
I'm being intentionally vague here. There are so many possibilities. Any pathway would have one or two of them involved.
The key points are:
  1. ligand binds, changes shape of receptor
  2. receptor changes shape on the inside of the cell too, changing it's interaction with the next protein in the pathway
  3. some biochemical change occurs, resulting in a change to the behavior of the cell.


More specific


We have looked at a small subset of G-protein-coupled receptors. These are among the oldest and most diverse types of signal molecules. We didn’t look at all the possibilities, just one or two.
There is a decent animation of G-protein signaling
here and a followup to the other steps we talked about here. The structural representation is not so good. But, it’s not too bad. Also, it chooses a slightly different version of what is going on. There are many variations on this theme.
It adds some more detail (I won’t ask about the “RGS,” or receptor inactivation, for example). However, it animates what we have discussed.
You may notice that there are many other animations for G-protein coupled signaling at You Tube. Some of them open ion channels (as in nerve cells), some of them connect to adenyl cyclase, as we have discussed. Others connect to other pathways.
The cAMP is the “second” messenger that goes off and activates many other proteins in the cell. Because each cell will have its own cAMP-responsive proteins,
each cell may respond differently to the same signal molecule.

How is the signal turned off? Well, ligand may leave the receptor..but that doesn’t stop everything that is happening away from the receptor. The G-protein is still active, as is the adenyl cyclase and there is a lot of the second messenger, cAMP still floating around. The G-protein turns itself off by hydrolyzing the GTP back to GDP and lets go of its target protein (in this case, the adenyl cyclase) That turns off the target protein. Well…you still have all that cAMP around.
There is another enzyme that destroys that, converting it to AMP (not cyclic anymore). That enzyme is phosphodiesterase, often abbreviated PDE.

  • In more general cases, you should be able to recognize the steps of signaling and what are the “downstream targets” given information about other pathways.
  • It would be good to know about some simple examples:

Other examples:

  • Receptor-tyrosine kinase, or RTK. These are receptors frequently for growth factors. One of the most interesting things about these is that they are NOT found in prokaryotes or even in unicellular eukaryotes. Tyrosine kinases seem to be specific to multicellular organisms (they appear to be used by those cellular slime molds when they form multicellular slug).
  • As their name implies, they add a phosphate to specific tyrosine residues. Typically, ligand induces two of them to come together and phosphorylate each other. The addition of the phosphate changes the shape of the protein a little, which makes them more active. They then phosphorylate tyrosine on specific target proteins (often kinases themselves) which then activate specific pathways.
  • These are usually receptors for "growth factors," peptides that stimulate cells to grow and divide, or "survival factors," signals needed to keep cells from dying.
  • Channel Proteins: These open channels to allow the passage of ions. Ions in turn control various cellular function.
  • The next three

    all work by coming together into a structure involving cytoskeleton that "recruits" specific enzymes. The receptor mediates the structure.
  • Death Receptors. pretty obvious what these do.
  • Non-receptor Tyrosine Kinases. Can signal various things…either cell death or gene regulation etc.
  • Cell Adhesion Receptors. Also self explanatory. These are the class I worked on for a decade or so.

Below are some examples of signal cascades. I just want you to be able to read one and make some predictions. So, for example, a protein called "Bcl 2" inhibits a signal that tells cells to go into apoptosis (cell death—it's near the bottom left). Some cancers show overexpression (make too much) of this protein and that leads to really aggressive tumors. Can you hypothesize why?
signal-overview



Other key words.


Autocrine: signal the “same cell.” A cell makes a signal molecule that signals itself, or its neighbors which are more or less the same cell. Epithelial cells making epithelial growth factor would be an example of this.
Paracrine: a cell secretes a signal molecule that binds to and signals other cell types. Platelet-derived growth factor stimulating the cells of the blood vessels and nearby endothelial cells would be an example of this.
Endocrine: these are hormones. By definition a hormone is secreted by an organ distant from the site of action. An endocrine hormone travels through the bloodstream to get to its target tissue.