01.07 Cell Signaling
- Cell signaling occurs when an external signal elicits an internal response
- Cellular communication happens
- Between an organism (or a cell) and its environment
- Between two organisms
- Between cells within a multicellular organism
- Phosphorylation is the key chemical reaction
- Insulin signaling
- When blood glucose levels go above 100 mg/dL, insulin is released into the bloodstream
- Signal: Insulin binds to specific receptors on the surfaces of muscle, fat and liver cells
- Response: Glucose transporters go to the cell membrane to let the excess glucose in
- Once inside the cell, the glucose has multiple possible fates: stored as glycogen, used to make pyruvate which can then be used for energy or be stored as fat
- The insulin signal transduction cascade
- The insulin signaling process can be likened to a cascade or waterfall: the upstream signal causes a downstream response
- When insulin binds, a series of events occur which involve many different proteins along with phosphorylation (see below)
- Eventually, glucose transporters that are bound by lipids are able to meld with the cell membrane, thus allowing glucose to enter the cell.
- Amplification of a signal can occur where one signal protein can cause 1000’s of molecules in the cell to react in a certain way
- Phosphorylation is the key reaction
- Because phosphates have a lot of negative charge, they can cause proteins to move
- Positively charge regions will come closer to the phosphate
- Negatively charged regions will be repelled by the phosphate
- Kinases are enzymes that put phosphates on Ser, Thr & Tyr OH groups, essentially turning the signal “on”
- Phosphatases are enzymes that remove phosphates, essentially turning the signal “off”
- Because phosphates have a lot of negative charge, they can cause proteins to move
- There are many different types of signaling and it is very complicated
- Some signaling pathways stay in the cytoplasm or near the cell membrane (like insulin described above)
- Other signaling causes genes in the nucleus to be expressed or silenced
- Phosporylation is a common reaction in these other pathways too
- Cell signaling is about communication so that the cell knows what it need to do to live
- A ligand binding its receptor is an external signal that can then create an internal response
- Insulin signaling for glucose transporters to enter the cell membrane is an example of a signal transduction cascade
- Phosphorylation is the key reaction that takes place during cell signaling
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Hey there, what we’re going to talk about today is cell signaling. The basic idea is that an external stimulus is going to lead to an internal response. Cell signaling is really about communication, communication between an organism and its environment, between organisms, or even among cells within a multicellular organism. And the reason why cells need to communicate, and know what’s going on outside of them, is because they need to be able to find food and find energy, they need to protect themselves, they need to know how to replicate themselves or when to replicate themselves. Those are some of the bits of information that they can get from their outside environment and what’s going on around them. There’s an important type of reaction that takes place in cells that can serve as the message, and this is phosphorylation. Remember what a phosphate looks like PO4^3-. We’ve got the 4 oxygens and the 3-….that’s what serves as the message.
This is a cartoon that was drawn by one of my biochemistry professors, way back when, and I just love it. I think it’s super cute. Here you can see the idea of the stimulus up here and then the response down here. What happens in between then is…when this little yellow fish guy comes in and binds, we get a message that gets transduced–which basically means information getting passed inside the cell. (This is outside here and this is inside the cell down here.) So that message gets passed through all these little fishies, all sorts of things happen, and eventually the little seahorse guys are going to pull open just a little bit, and it would allow something like calcium, in this case, to come rushing into the cell.
There’s a bit of terminology that I’d like to tell you about here. One is this idea of it being a ‘cascade’. And so it’s like a waterfall. And so we would think of parts that are up higher here. this is upstream on this side, and down here would be downstream. Okay…upstream and downstream. And then another word that’s good to know is the word ‘ligand’: a ligand binds a receptor. Some people say ligand (like eye), but either way. So a ligand binds the receptor. That’s what really starts the whole thing off.
Let’s look at this type of thing in a real biochemical example. What we have here is insulin binding to the insulin receptor. So insulin is the ligand binding to its receptor. And then you can see how complex the messaging gets down under here…we’ll go into some detail on what’s going on with all these little gray circles in a moment. If we follow these little arrows, we see that all sorts of things happen: things bind, they release, they bind again, they release, they move, go to different places, different things happen, new guys come in…eventually we make it over to this thing here: these little green things, those are lipids. They’re just like the lipids that are in the cell membrane over here, but they’ve got glucose transporters embedded in them. So as the signal comes in, it says, “Hey, glucose, transporters: go up to the membrane and meld with the membrane”. And that embeds the transporters in there. That’s what allows the glucose to come into the cell. Insulin is causing transporters for glucose to come to the cell membrane and allow the glucose to come in.
One thing that I’d like to point out about this is the idea of amplification. In this particular scenario, we see one insulin molecule resulting in say three of these little glucose transporters coming here to the surface. In reality, it would be thousands. One little external molecule can lead to thousands of molecular responses down inside the cell.
Now let’s look at this blown up area that has all those little gray circles. So what’s going on here? So this guy is an ATP. And what happens if we follow the arrow, it comes in and leaves one of those gray guys behind, and then it turns into ADP. So what is happening there to that extra little P…we’ll just put it over here. What’s happening to this P? It ends up getting put onto amino acid side chain residues within the protein. This little red guy is a protein…all of these things are proteins here. There are specific residues that can accept the P. These are serine that has just a hydroxyl, threonine which has a CH3 and an OH. And then the other one is tyrosine, which has an aromatic group and an OH. All three of them have these OH groups. What can happen is that this OH, that belongs to the amino acid that is going to get attached to the phosphate, so that’s what is being represented here by all these little gray circles. You’ve got phosphates attaching to proteins.
Why is that so important? Well, negative charges like this repel. Let’s say there’s a region of a protein that’s got some negative charges in it. It’s going to be completely repelled by this. Remember these are going to repel one another. So they don’t like to be close to each other. That’s going to move this section of protein away. But meanwhile, there may be some other portion of, maybe some other protein, that’s going to be positive…”Ooh, I like this, there’s negative charges over here.” And so it’s going to be attracted to the phosphate. Altogether, what that means is it causes movement. Movement is the key thing that’s happening through this picture. So maybe right here, when these two get attached here. So remember this guy, he starts out here by himself. And then maybe when these phosphates got attached up here to this upper protein, this one was attracted to it because maybe it had some positive charges right here. So that got attracted to it. But then it gets phosphorylated again, down here with some negative charges. And now it’s attracted to this thing over here because maybe there’s positive charges there. So we just have movement taking place in here.
It’s important to know these two words: kinase is going to be the enzyme that puts the phosphates on, but there’s only a certain amount of time that that’s going to last because then a phosphatase phosphatase is going to come along and take it off. We think kinase puts P on and phosphatase takes P off. And so that’s how this can be…dynamic is because there’s an interplay of the kinases and the phosphatases, adding the phosphates, taking them off, making things move around. And then that’s why there’s just so much movement in the, in the signal transduction cascade.
As complex as that was, let me show you here what just even a snippet of how much more complexity there is in terms of the grand scheme of things with signal transduction. What we looked at was just an example of a receptor tyrosine kinase pathway, similar to this one right here. But what we looked at with insulin….insulin does all sorts of other things, too. It’s not just about bringing the glucose transporters to the membranes. There are other ones: G protein coupled receptors (GPCR)…that would be this type. And there’s other types of receptor tyrosine kinases. Then you’ve got Integrins, and the Wint pathway, the Hedgehog pathways. And cytokines can communicate with from the outside to the inside. There’s so many different ways of having signals from the outside get transduced to the inside.
But one thing that ties it all together though is, if you notice all those Ks, we’ve got lots of Ks in here–lots and lots of Ks. That’s because these things are all kinases. So they are the things putting those phosphates on the protein. So it really is the common language throughout signal transduction. And then one other thing I’d like to point out: this is the nucleus down here. Often the signal from the outside is going to get transduced all the way down into the nucleus, and that’s going to allow certain genes to get turned on, or certain genes are going to get turned off. There’s a direct relationship then between the outside and the nucleus in gene expression.
To summarize: Communication happens between cells, between cells within organisms, between organisms and environment, cells and environment, et cetera. The basic idea is that an external stimulus is going to lead to an internal response. The example that I gave was insulin as a ligand…it can help bring glucose transporters to the membrane to allow glucose to enter a cell. The last thing was how important phosphorylation is. That’s that key biochemical reaction that takes place during signal transduction.
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