Illustrating the complexity of signal transduction with a MAPK pathway. How mutations in the pathway are linked to cancer.
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- In the diagram at5:04, what is the significance of that link to Alzheimer's?(9 votes)
- 4. Cancer is generally linked to a failure of cells to respond to "death signals", and their subsequent over-production. When a ligand binds to a receptor, the response of the pathway is to deactivate a capase inhibitor, allowing capase to become active. Capse then goes through a phosphorlyation cascade that ends up in the death of a cell. If a cell is mutated to a point where it cannot relieve death signals, or can't complete the signal transduction pathway, the cell will continue to live and divide.
5. When the effects of number 4 occur along with errors in mitosis pathways (for instance, when Sal mentioned the mutation in RAS causing increased mitotic rates) , mutated cells grow quickly and cannot be killed by apoptosis pathways, and thus they have free range to spread locally or metastasize.(12 votes)
- Why aren't the receptors shown in any cell anatomy?(3 votes)
- When looking for cancer treatments are they looking for ways to stop the MAP-kinase cascade or are they looking for ways to inactivated the ras protien?(2 votes)
- There are thousands of different types of cancer and no one treatment helps with all of them.
While, about a third of human cancers are though to involve Ras and it is a subject of research, so far there don't seem to be any effective treatments targeting Ras.
The whole MAP kinase pathway is apparently difficult to target, but work is on going:
Does that help?(4 votes)
- How can a signal transduction pathway branch off into multiple parts? Isn't there only 1 signaling molecule?(3 votes)
- What is the orange and the blue?(1 vote)
- The orange is the cell membrane, and the blue is the nuclear membrane - if you look close, the membranes are made out of their names in the video.(3 votes)
- Just for clarification: when Sal was speaking of the Rat Sarcoma he said that the cancer prevented the stop cells from communicating. How would this effect the rat. Would it grow exponentially or would there be no visible change?(2 votes)
- It affects the rat in any form of cancer.
The place of growth of the tumor and eventually later metastasizing is selected by the cell in which errors are occurring. You know that even one single cell is enough to grow tumor on that part of your body.
If that rat was exposed to cancerogenic factors such as X rays, the number of errors would enormously build up and potentially many tumors will grow all over the body.(1 vote)
- what's the point of such a long and complex pathway? why can't the enzyme that performs the cellular response just be immediately activated, without the need of a series of conformational protein changes? is there a reason other than signal amplification?(1 vote)
- Yes. Because that way metabolism would be even more complicated. What do I mean by that?
Just activating separating enzymes for separating signals would be consuming and robust for our brains and bodies to control. It would be energy and time-consuming and hard to switch from one to another.
This way is cost-effective and time-efficient for our bodies.
I will illustrate it with the example of fighting cancer.
Although originally designed to inhibit a single kinase, several small molecule inhibitors target several, often related, kinases. When used to treat tumours bearing activating mutations in a single kinase, these 'promiscuous' inhibitors have shown clinical effectiveness and less toxicity than expected. This effect may stem from their capacity to inhibit several kinases in a signalling 'network'. However, another possibility is that these broad-spectrum inhibitors inhibit kinases that might be activated by subsequent mutations.
Now the problem of 'complex signalling pathway' bothers researchers when choosing methodology on how to study pathways and molecules. how to use genetic manipulations to overcome these difficulties. Phenotypes generated using traditional 'knockout' techniques—which completely ablate expression of a signalling protein—represent the aggregate consequence of disrupting all functions of, and severing all communication facilitated by, that protein. In contrast, more refined 'knock-in' techniques—which insert a discrete mutation into only one region of a protein—allow controlled manipulation of specific protein functions and signal interconnections.
I can say in a few words that having complex system is good because that way one signalling molecule (let's take cAMP) can shut down or turn on multiple other enzymes and cascades.
That way body only makes an effort to produce the first initial second messenger. The job is done. cANP binds to many different kinases and initiates 7 different processes!
Imagine if it was 'easy' and 1 molecule regulated one enzyme. The body would have to produce 7 different molecules (second messengers) for 7 different kinases. Speaking of the same scenario.
- [Voiceover] In previous videos on cell signaling, we talk about the idea that if we have a cell right over there and let's say it has some type of receptor. It doesn't actually have to be on the cellular membrane, but I'll put it there for now. It can bind to some ligand, that when the ligand binds to the receptor and it's usually particular, the ligand is usually particular to the receptor and vice versa, it can set off a whole cascade of events. In particular, once it binds, so let me actually draw the ligand bound to the receptor, you can have a signal that tells the cell to do something. It might activate some genes, it might change the metabolism of the cell in some way. And this signal that goes from the receptor into the cell to make the cell behave in some way, we call that signal transduction. We call it transduction, signal transduction. In the previous video, I was kind of hand wavy about it, and you might have been saying, "Well how does a signal actually go into the cell? "How does it actually move through the cell "and how does it actually make things happen?" And what I wanna do in this video is I'm not gonna go into all of the details, but I'm gonna give you an appreciation for how transduction can actually occur. Hopefully it'll also give you appreciation for how complex biological systems, including you and me, and even each of our individual cells actually are. So this pathway that we're seeing up here, and you can see that there's a bunch of pathways that all kind of work together and overlap in terms of the enzymes and the proteins that are involved. This, as the diagram calls, is the Classical Map kinase pathway. If you're wondering, "What does Map kinase stand for?" And oftentimes people will just say MAPK or M-A-P-K, it stands for mitogen, M for mitogen, mitogen-activated protein kinases. And you might be saying, "What does mitogen mean?" Well, mitogen refers to things that cause cells to mitose, to actually go into mitosis, to start replicating themselves. Now, what is mitogen-activated? So this pathway is going to be activated by a mitogen. Mitogen-acivated protein kinase. Well, a protein kinase, a kinase, and we've seen kinases multiple times. They're involved in many, many, many biological mechanisms. These are general term for enzymes that help take a higher energy phosphate, or especially, I should say, a higher energy bond or a phosphate, part of an ATP or a GTP and transfers them to different molecules, and as they transfer them to different molecules, it's able to leverage that energy to actually facilitate some type of a mechanism. Now, as I said, I'm not gonna go into all the details here. This is actually quite complex, but I want to make a little bit sense of it. And we're actually gonna talk about a few proteins and a few enzymes that are actually fairly important to modern biological research. So what you have right over here, I'll start with this molecule right over here. This is the ligand. This is the ligand, it's going to be released by some other part of the biological system, from some other cell. And this EGF, this stands for epidermal growth factor. The 1986 Nobel Prize in medicine was actually given for the discovery of EGF, of epidermal growth factor. Now this is going to be the ligand, and this is essentially when this attaches or when this binds to a receptor, that's going to cause a signal to be transduced. You're gonna have the transduction going into the cell. And so you can imagine, it's going to bind to this membrane receptor, and so EGFR literally stands for epidermal growth factor receptor, EGF receptor. And it's part of this protein complex and once this binds, it's able to help activate RAS right over here. RAS, once again, all of these names, they have these interesting histories associated with them. This stands for rat sarcoma, and sarcomas are cancers in certain tissues in the body. It was first discovered associated with certain cancers, that rats that had certain sarcomas, that they were able to see that there were mutations in the genes that produced the RAS protein. Because of those mutations, the RAS protein that the enzymes associated with it were in their activated mode. And because they were in the activated mode, this mechanism was kind of overactive. And any of the stop signals weren't actually happening. And so you could imagine a mechanism right over here that is about cell differentiation, that if this mechanism proceeds, it's eventually going to tell the DNA, some portions of the DNA, especially the portions of the DNA that are involved with DNA replication, with cell division, with mitosis, those are gonna go crazy, and that's exactly what happens in cancer. So this pathway is actually a very important pathway in cancer. You see right over here, you actually see the Map kinase, it's often called, or was originally called ERK, which is extracellular signal regulated kinase. But this in an incredibly important pathway to cancer researchers, and they actively are looking for different types of drugs, different types of molecules that can down regulate this type of pathway. So the whole point of this video, once again, I'm not going into all of the details on the Map kinase pathway, was to give you an appreciation for how complex transduction is. You have this cascade of this signal which is really these phosphate groups originally transferred from a GTP going to Ras, and it keeps cascading down all the way until you actually have the DNA being told to, or you start activating mechanisms where the DNA is going to start replicating, and then the cell itself is going to proliferate and differentiate. This needs to happen in practically every cells in our body, but there's all sorts of kind of factors that keep it from going crazy. But if you have a mutation in something like the Ras gene which codes for the Ras protein, then you could end up with an actual cancer cell. So hopefully this give you a little bit more appreciation for how transduction actually occurs.