Hi in this video we're gonna be talking about protein kinase receptors. So first let's focus on their structure and how they're activated and then we'll get into some more details about what protein penises are and how they work. So protein penises or protein kinase receptors you're gonna sometimes see these as enzyme coupled receptors but exactly the same thing. But they're trans membrane protein receptors and they are activated through binding a ligand very similar to any other receptor on the plasma membrane. Now there are two main types of kindnesses. Remember what Aquinas does, it's going to add a phosphate. This is really big function of this protein. So receptor penises are the ones that we're most familiar with and the ones that we're going to focus on the most and these are kindnesses that are receptors first and they contain keenness activity on the side of solid surface, meaning that there are the part of the protein that's in the side of saul that's the part that has the ability has this enzymatic ability to add phosphates. And so there are two classes. These include receptor tyrosine kinase is which is the largest class and it also recruits receptor Syrian theory and sinuses. Um and these are different. These are amino acids in case you don't recognize them. And so that just means the different types of amino acids. These kindnesses phosphor alike. I said names based on the menu acid they fast for like then you have a second class this is the non receptor kindnesses and these are kindnesses that bind to a receptor when the receptor has been activated by a ligand. So everything is connected to the plasma membrane into proteins within the plasma membrane. It just matters where the keenness is. Is it actually on the protein that's in the membrane which is the receptor or is it somewhere in the side of saul but gets recruited to this receptor when the receptor binds a leg in. So here are your two types of receptor you have, your receptor kindnesses you can see here's the ligand that binds and then you have these regions here on the side of solid side that have the ability to add phosphates. And then you have the non receptor kindnesses which once the ligand binds just here. So once this comes down here and binds then you have some type of kindness that's in the side of salt that will come up and bind as well. And so activation of both of these pathways is triggered through um receptor phosphor relation. So ligand binding um can cause the receptor piracy kindnesses to find to each other and form a dime er and the phosphor relation that happens happens because the one receptor, one half of the dime er is gonna phosphor late the other one. So this is a process called trans auto phosphor relations, you may not necessarily need to know that term but in case you hear it, that's what it means. It means. One of the receptors that's in this dime er phosphor relates the other and you can see this here in this image here. So we have this phosphor relation which was caused from this one and then we have this phosphor relation which this side caused. So the trans auto phosphor relation. Now once this protein is correlated all these other types of intracellular signaling molecules can be recruited to these tales that are now phosphor related. So here's some examples of things that can that can come there once that tails phosphor related one classes adaptor proteins. These are going to adapt different signaling proteins to each other and form some type of signaling complex. You have docking proteins and these service docking sites for other proteins Makes sense. You have transcription factors which actually can be recruited here and activated and then eventually go back to the nucleus and then also any other type of signaling enzyme that may act in a pathway can be recruited here. So um proteins that bind to these phosphor related regions on these kindnesses or these receptor kindness is usually have a domain called an S. H. Two domain and this is just gonna be an amino acid sequence that's found on signaling molecules which bind um phosphor related amino acids usually tyra scenes and so they're recruited to foster related tire scenes which are really commonly found on receptor protein highnesses and that's how these proteins are recruited there. So here's an example of intracellular signaling molecule recruitment. So here you have a ligand, you don't need to know any of these abbreviations, so just kind of scribbled without but you have this ligand, it's blue, you don't need to know its name. It binds to this receptor. This recep the results in phosphor relation. So you have your dime er you want and you're too and they phosphor late each other once here these proteins can be recruited to these areas and serve these sort of intracellular signaling complexes which then go on to signal a variety of different things and can really affect the sell through gene transcription or however it's gonna affect the cell. So that's kind of an overview of how receptor protein kindnesses or other protein kindnesses work in these complex signaling pathways in the cell. So with that let's now move on.

Okay. So now we're going to talk about how we would inhibit the receptor activation and signaling. So receptors get activated and they're like whoa yeah signaling. But eventually that's a little much for the cell. And the cells got to say, okay, stop. So it tells the receptor to stop in four ways. The first is through receptor mediated into psychosis. So we've talked about receptor mediated in psychosis. What this does is it just internalizes the receptor and once that's once it's internalized it's no longer on the plasma membrane and so therefore it can no longer signal. Now some of that receptor will eventually get degraded but eventually most of it will be returned to the plasma membrane so that it can signal later when the cell wants it to again. But that's the first way of down regulating the signal. Just remove it from the plasma membrane. The second is kind of connected. That's just license um well degradation. So if you don't want the receptor anymore and you're not gonna need it in the future then the cells just gonna degrade it. Then you have a phosphor tires and phosphate Asus and this is actually so first you remember what a phosphate taste does, right? So it's gonna remove phosphates. And if you were really really, really smart you would have noticed that I gave you the answers right here removes phosphates but these phosphate tyrosine phosphate specifically remove phosphates from receptor tyrosine kindnesses um in order to inactivate them and then finally you have this other proteins called socks and they terminate signals from special receptors that we haven't talked about yet but are going to talk about. And these receptors are called cytokines receptors. Um and they have cytokine signaling molecules. And so socks proteins are the way that they get down regulated or one of the ways. Um so just know about them even though we haven't really talked about the cytokine receptors yet. We're going to talk about them soon. So here's your methods of receptor inhibition. So we have this activated receptor up here that's like signaling throughout the cell. So it's going signaling throwing a big signaling party but the cell doesn't really want that. And so the cell is like whoa stop so how the salad is going to get this receptor to stop. Just like freaking signaling everywhere. One of the ways it can do it is it can take it off the plasma membrane so that internalizes it into the end zone. Once it's in the end zone it's no longer signaling because it's no longer on the membrane but it can through receptor mediated apoptosis in the recycling pathway, be recycled back to the plasma membrane if it's needed. It could also get degraded in the license zone if it's not going to be needed ever again. Um or it can be um or foster retire seen phosphate assis can actually just remove the phosphate while it's still on the plasma membrane and then turn it into an inactive receptor and then we also have these proteins that we haven't talked about yet, the socks proteins, which work on the side of kind receptors. But we're going to talk about those very soon. So that's how the cell tells the signaling the active receptors to just stop. So with that let's not move on.

Okay so now we're going to spend some time talking about some of these common receptor protein signaling pathways that you're going to hear about in your lecture, you're going to hear about your book and you're going to wonder oh my gosh how are these all separated? And what do all these like weird proteins mean? Well we're going to go through them very clearly. Just so you understand which pathways everyone's talking about. So the first pathway is gonna be really this activation of wrasse pathway. So what is grass? Well, grass is gonna be a GTP binding protein. So it binds GTP and it's super important in signaling because it's this major signaling hub. It's kind of like the Grand Central station of signaling. I mean Wrasse is pretty much activated by every receptor tyrosine, Tyr skin, tire scene Kindnesses and they all activate rafts. And then um this is really important. And a lot of research has gone into this not only because it's like the Grand Central station but also because Ross is actually mutated and around 30% of all cancers. So when Ross is mutated, bad things happen and because it's this major sorting hub so people study it and therefore you need to know about it for symbology. So how grass works. Like I said it binds GTP which means that it's gonna cycle through an active state where it's bound to GTP and an inactive state where it's bound to G. D. P. And this is common, we've seen this over and over and over again. So you know we keep saying it's gonna keep we're gonna keep seeing it. And so um how does ralph actually just originally get activated? But one of the ways is through auto phosphor relation of an RTK. So an R. T. K. Is gonna bind a leg in. When I say R. T. K. I mean receptor tyrosine kinase it's gonna bind a Liggan that's gonna dime arise, it's gonna become active, it's gonna auto phosphor relate itself one those false correlations have happened then um Wrasse will get recruited there or some other signaling protein will get recruited there and eventually make it to harass. But eventually once that signal reach wrasse then rats will be activated. Which means that it's going to switch from G. D. P. Two G. T. P. So when ross is activated it falls for relates a number of pathways. But the one that we're going to focus on because the one that your book focuses on and that's going to be this cascade of searing Karen in protein penises. So the most common of this is the map keen signaling pathway. And so in an really unimaginative way of naming this. So wrasse is going to actually activate this protein called Map keenness keenness keenness and you're like why is why is it repeated? Is that a typo, no it's actually called matt keenan they repeat it three times and that's to separate the next member of the pathway. Which map Keynes Keynes Keynes phosphor relates which is called matt cain cain. So here we have two and then matt Keynes Keynes goes onto phosphor late and activate map keenness. So this is one. So you have wrasse going to the map KKK to the map K. K. To the map K. 321 and then once we each one of these including this one and all of its other ones 321. All of these different map kindnesses can go on to foss for like different nuclear proteins which regulate gene expression. So an example that you may see in your book is a transcription factor called june um june does a lot of things. We're not going to talk about them right now but just know that june is a transcription factor. So it's going to regulate gene expression. So here's an example of the map kinda signaling pathway. So you have wrasse, it's become activated because it has a G. T. P. That's how we know it's activated. It then activates the map three kindnesses. Then the two kindnesses then the one kindness and that goes on to activate other proteins which affect gene expression. So that's how that pathway works. Now we're going to talk about also the RTK activation of phosphor and also tied three kindness. And this works by foss relating in a hospital fossil lipids. So I'm like repeating words that you probably don't remember and you're like oh my gosh! These words are so complicated but they're not because in a hospital fossil lipid is just a type of lipid found on the plasma membrane. And this is a kindness. And we can abbreviate these two P. I. Three kindness. And also to all false for lipids. And we've seen this before. I don't know if you remember but we have seen these lipids before and when we talked about the G. Protein coupled receptors but they act so Archie case once activated can activate this P. I. Three kindness. Um And fox correlate these lipids in the plasma membrane. So why is that important? And why am I even talking about that? Well because this phosphor relation of these lipids and of these proteins here can serve as this docking site for other signaling proteins. So one of the signaling proteins that I want to talk about is the protein kinase B. Um You may see this as a K. T. And what a Katy does is it goes on to inhibit bad. Bad as a protein and Bad is a protein that when it's really activated it causes cell death. Which is why it's bad right? The cell doesn't want to die. Um But bad stimulates death. So protein keenness works by or a K. T. Works by inhibiting bad and therefore inhibiting cell death also called apoptosis. So it promotes survival. Then you have the second pathway. This is phosphate based C. And this results in the formation of I. P. Three and dag which I've explained what these are. So I'm not going to go through that again. Um But if you don't remember, feel free to check out the G protein coupled receptors where I talk about it. Or the hospital foster lipid signaling pathway video where I talk about it as well. Um But the purpose of this is just to say you know this an asado hospital pathway is activated by Archie case as well which go on to do a lot of things including promote survival. Well I don't want to do that, let's cancel that. So here we go. So here's the P I three K A K T. Get my thing back. P three K K. T. Bad pathway. So you have this receptor tyrosine kinase it becomes activated with the phosphate. This activates a. P. I. Three kindness which activates A. K. T. Which inhibits bad and promotes survival by preventing apoptosis. So that's the second pathway. So now let's talk about this third pathway that we're going to talk about in this video and that's gonna be the transforming growth factor beta pathway. And this pathway is going to be activated by searing theory. Mean kindnesses. And so how this works is you have a Liggan called T G F. And this binds to the T. G. F receptor makes sense. Like we've said before now, once the ligand binds the receptor that's going to result in what it's gonna result in demonization of two different types of Syrian theory and the first type, which we're going to say type two and we type two is going to be phosphor related by the first type, Type one. But type one is important because it initiates this signal transaction cascade by phosphor relating type two. Eventually there's a lot of different intermediates here which we're not going to go over but eventually somewhere in the pathway this results in false correlations and activation of proteins called mads, which are transcription factors. Now I get that this is all super complicated. I'm using a bunch of abbreviations here but hopefully these pictures will help you out and what is happening and what's going on. But it is important that, you know, actually all these bolted terms because um you might be quizzed on them or test on them because these pathways are really important pathways. I mean there's hundreds of pathways that we didn't talk about but these are the really important ones that you're just gonna have to know. Um And so I mean biology is memorization a lot of the time. So this is just something you're gonna have to memorize. So how this happens, you have T. G. F. It binds to this receptor, this receptor eventually down wherever it's going to activates. Mats and mats are transcription factors which support gene expression. So those are the three most common pathways that we're going to talk about. So with that let's now turn the page

Okay, so in this video we're going to focus on the non receptor protein, coyness is specifically using the jak stat pathway as an example, get lots of words but I'm going to walk you through it. So the jak stat pathway is going to be a pathway. You're going to have to know about it. You're going to read about it in your textbook, you're gonna see it in lecture because it's a great example of these non receptor tyrosine kindnesses which other than briefly mention them mentioning them previously. I haven't talked about it all because they're not a big class, They're not the largest class. Um but we didn't need to give you at least one example of them. And so this is it the jak stat pathway. So how this happens is there are these molecules called cytokines and these are the Liggins and cytokines end up coming and binding to a cytokine receptor. So I said that I was going to mention these receptors later and so here is the short video on these receptors and this pathway. So these Liggins called cytokines come in and buy into the cytokine receptor on the plasma membrane. What happens is there's this kindness recruited? Remember the keenness on these these receptors is not actually in the receptor, it's it has to be in the side of salt, it has to be recruited. So the keenness here is going to be the Janice keenness. So this Janice keenness gets brought to the receptor and it activates the receptor. Once the Ligon has been bound now now you have this complex of the receptor of the ligand and the Jack. So what Jack does is Jack recruits a lot of different proteins. But the main one that we're going to talk about is stats and stats are transcription factors. So Jack recruits, they phosphor late, they activate this family of transcription factors. And so once stats are activated they then disassociate travel to the nucleus and effect gene expression. Now I talk about the Jak stat pathway and you may think, oh it's just Jack and just stat but it's actually not. These are families of proteins. So there are actually four jacks and six stats which can interact and regulate and work with different combinations to regulate different signaling pathways in different gene expressions. So it's not just Jak and stat, it's much more complex than that with all these different combinations that can form. But to just review this what you see is you have your leg in it's called a cytokine. It comes in and bind to the cytokine receptor. Once that's here, Jack is going to be recruited and it's going to foss for a late because it's a kindness and activate this receptor. Once that is active stat will actually be recruited here and remember stat is gonna be a transcription factor. So then once they're activated they're like well I don't need to be here anymore. I need to go do my job. So they leave and travel to the nucleus where they affect transcription and gene expression. So that is the main example for the non receptor tyrosine penises, because Jack is not a receptor, but it is the kindness and also the cytokine receptors that I said I was going to briefly mention later. So with that, let's not turn the page.