Protein Kinase Receptors: Videos & Practice Problems

Protein kinase receptors, including receptor tyrosine kinases (RTKs) and non-receptor kinases, play crucial roles in cellular signaling. RTKs activate through ligand binding, leading to dimerization and transautophosphorylation, which recruits various intracellular signaling molecules. Key pathways include the RAS pathway, which is vital in cancer research, and the JAK-STAT pathway, involving cytokines and transcription factors. Inhibition mechanisms include receptor-mediated endocytosis and phosphatases that deactivate signaling. Understanding these pathways is essential for grasping cellular communication and regulation.

Structure and Activation

Hi. In this video, we're going to be talking about protein kinase receptors. First, let's focus on their structure and how they're activated, and then we'll delve into more details about what protein kinases are and how they work. Protein kinases or protein kinase receptors, you're going to sometimes see these as enzyme-coupled receptors, but they are essentially the same thing. They're transmembrane 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 kinases. Remember what a kinase does; it's going to add a phosphate. This is a significant function of this protein. Receptor kinases are those we're most familiar with and will focus on the most. These are kinases that are receptors first, and they contain kinase activity on the cytosolic surface, meaning that the part of the protein that's in the cytosol has this enzymatic ability to add phosphates. There are two classes. These include receptor Tyrosine Kinases, which is the largest class. And it also includes receptor Threonine Kinases, which are different; these are amino acids in case you don't recognize them. That just means the different types of amino acids these kinases phosphorylate. I use that name based on the amino acid they phosphorylate. Then you have a second class. This is the non-receptor kinases. These are kinases that bind to a receptor when the receptor has been activated by a ligand. So everything's connected to the plasma membrane and to proteins within the plasma membrane; it just matters where the kinase is. Is it actually on the protein that's in the membrane, the receptor? Or is it somewhere in the cytosol but gets recruited to this receptor when the receptor binds the ligand? Here are your two types of receptor. You have your receptor kinases. You can see here's the ligand that binds. And then you have these regions here on the cytosolic side that have the ability to add phosphates. And then you have the non-receptor kinases, which once the ligand binds, as shown here. So once this comes down here and binds, then you have some type of kinase in the cytosol that will come up and bind as well. Activation of both of these pathways is triggered through receptor phosphorylation. So ligand binding can cause the receptor Tyrosine Kinases to bind to each other and form a dimer. And, the phosphorylation that happens occurs because one receptor, one half of the dimer, is going to phosphorylate the other. This is a process called transautophosphorylation. 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 dimer phosphorylates the other. You can see this here, in this image here. We have this phosphorylation, which was caused by this one. And then we have this phosphorylation, which this side caused. So the transautophosphorylation. Now, once this protein is phosphorylated, all these other types of intracellular signaling molecules can be recruited to these tails that are now phosphorylated. Here are some examples of things that can come there once that tail is phosphorylated. One class is adapter 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 serve as docking sites for other proteins. It 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. Proteins that bind to these phosphorylated regions on these kinases, or these receptor kinases usually have a domain called an SH2 domain. This is just going to be an amino acid sequence that's found on molecules, which bind phosphorylated amino acids, usually tyrosines. So, they're recruited to phosphorylated tyrosines, which are commonly found on receptor protein kinases. 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 scribble those out. But you have this ligand, it's blue. You don't need to know its name. It binds to this receptor. This receptor results in phosphorylation, so you have your dimers. You have your 1 and your 2, and they phosphorylate each other. Once here, these proteins can be recruited to these areas and serve these sorts of intracellular signaling complexes, which then go on to signal a variety of different things and can really affect the cell through gene transcription or however it's going to affect the cell. So that's kind of an overview of how receptor protein kinases, or other protein kinases, work in these complex signaling pathways in the cell. So with that, let's now move on.

Inhibition

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, woo, yay, signaling, but eventually, that's a little much for the cell and so the cell's got to say, okay, stop. So it tells the receptor to stop in 4 ways. The first is through receptor-mediated endocytosis. So we've talked about receptor-mediated endocytosis. What this does is it just internalizes the receptor. And 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 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 this signal, just remove it from the plasma membrane. The second is kinda connected; that's just lysosomal degradation. So if you don't want the receptor anymore and you are not gonna need it in the future, then the cell is just gonna degrade it. Then you have phospho-Tyrosine Phosphatases, and this is actually first, do you remember what a phosphatase does? Right. So, it's going to remove phosphates. And, if you were really really really smart you would notice that I gave you the answer, it's right here, removes phosphates. But these phosphotyrosine phosphates specifically remove phosphates from receptor tyrosine kinases, in order to inactivate them. And then finally, you have these other proteins called SOX. 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 cytokine receptors, and they have cytokine signaling molecules. And so, SOX proteins are one of the ways they get down-regulated. 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, yay, signaling. It's throwing a base signaling party. But the cell doesn't really want that, and so, the cell is like woah, Stop. So, how is the cell 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 endosome. Once it's in the endosome, it's no longer signaling because it's no longer on the membrane, but it can, through receptor-mediated endocytosis and the recycling pathway, be recycled back to the plasma membrane if it's needed. It could also get degraded in the lysosome, if it's not going to be needed ever again, or it can be, or phosphotyrosine phosphatases 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 SOX proteins, which work on the cytokine 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 now move on.

Common Pathways

Okay. So now we're going to spend some time talking about some of these common receptor protein kinase signaling pathways that you're going to hear about in your lecture, you're going to hear about in 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 going to be really this, activation of RAS pathway. So, what is RAS? Well, RAS is going to 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, RAS is pretty much activated by every receptor tyrosine, not tyroskin, tyrosine kinases. And they all activate RAS, and then, 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 RAS is actually mutated in around 30% of all cancers. So when RAS 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 zoology. So, how RAS works, like I said, it binds gtp, which means that it's going to cycle through an active state where it's bound to gtp and an inactive state where it's bound to gdp. And this is common, we've seen this over and over and over again. Some, you know, we keep seeing it. It's going to keep we are going to keep seeing it. And, so, how does RAS actually just originally get activated? Well, one of the ways is through, autophosphorylation of an RTK. So, an RTK is going to bind a ligand, When I say RTK, I mean receptor Tyrosine Kinase. It's going to bind a ligand that's going to dimerize, it's going to become active, It's going to autophosphorylate itself. Once those phosphorylations have happened, then, RAS will get recruited there or some other signaling protein will get recruited there, and eventually make it to RAS. But eventually, once that signal reaches RAS, then, RAS will be activated, which means that it's going to switch from GDP to GTP. So, when RAS is activated, it phosphorylates a number of pathways, but the one that we're going to focus on, because it's the one that your book focuses on, and that's going to be this cascade of serine, the renin protein kinases. So the most common of this is the MAP Kinase signaling pathway. And so, in a really unimaginative way of naming this, so, RAS is going to actually activate this protein called MAP Kinase Kinase Kinase. And you are like, why is it repeated? Is that a typo? No. It's actually called MAP Kinase Kinase Kinase. They repeat it three times. And, that's to separate the next member of the pathway, which MAP Kinase Kinase Kinase Phosphorylate, which is called MAP Kinase Kinase. So here we have 2, and then MAP Kinase Kinase goes on to phosphorylate and activate MAP Kinase. So this is one. So you have RAS going to the MAP KKK to the MAP KK to the MAP K. 3, 2, 1. And then, once we each one of these, including this one and all of its other ones, 3, 2, 1, all of these different MAP kinases can go on to phosphorylate different nuclear proteins which regulate gene expression. So an example that you may see in your book is a transcription factor called June. June does a lot of things, not gonna 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 Kinase Signaling Pathway. So, you have RAS, it's become activated because it has a GTP, that's how we know it's activated. It then activates the MAP map3 kinases, then the 2 kinases, then the 1 kinase, 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 phosphatidylinositol 3 kinase. And this works by phosphorylating inositol phospholipids. 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 phosphatidylinositol is just a type of lipid found on the plasma membrane, and this is a kinase. And we can abbreviate these to PI 3 kinase and inositol phospholipids. And we've seen this before. I don't know if you remember, but we have seen these lipids before in, when we talked about the G-coupled receptors. But, they act so RTKs, once activated, can activate this PI3 Kinase and phosphorylate these lipids in the plasma membrane. So why is that important and why am I even talking about that? Well, because this phosphorylation 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, you may see this as AKT. And what AKT does is it goes on to inhibit BAd. BAd is 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 wanna die, but bad stimulates death. So protein kinase works by or AKT works by inhibiting bad and therefore inhibiting cell death, also called apoptosis, so it promotes survival. Then you have the second pathway, this is phospholipase C, and this results in the formation of IP3 and DAG, which, I've explained what these are, so I'm not gonna go through that again. But if you don't remember, feel free to check out the G protein-coupled receptors, where I talk about it, or the inositol phospholipid signaling pathway video, where I talk about it as well. But the purpose of this is just to say, you know, this inositol phospholipid pathway is activated by RTKs as well, which go on to do a lot of things, including promoting survival. So here we go. So here's the PI3K-AKT-BAD pathway. So you have this receptor Tyrosine Kinase. It becomes activated with a phosphate. This activates a PI 3 Kinase, which activates AKT, which inhibits BAd and promotes survival by preventing apoptosis. So, that's the second pathway.

Now, let's talk about this third pathway that we're going to talk about in this video. And that's going to be the transforming growth factor Beta pathway. And this pathway is going to be activated by serine threonine kinases. And so how this works is you have a ligand called TGF, and this binds to the TGF receptor. Makes sense like we've said before. Now, once the ligand binds the receptor that's going to result in what? It's going to result in dimerization of 2 different types of serine threonine kinase. The first type, which we are going to say type 2, and we type 2 is going to be phosphorylated by the first type, type 1. But, type 1 is important because it initiates this signal transduction cascade by phosphorylating type 2. 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 phosphorylation and activation of proteins called SMADs, 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 in what is happening and what's going on. But it is important that you know actually all these bolded terms, because, you might be quizzed on them or test on them, because these pathways are really important pathways. I mean, there are hundreds of pathways that we didn't talk about, but these are the really important ones that you're just going to have to know. And so, I apologize memorization a lot of the time. So, this is just something you're going to have to memorize. So, how this happens is you have TGF, it binds to this receptor. This receptor eventually down wherever is going to activate SMADs. And SMADs are transcription factors which support gene expression. So, those are the 3 most common pathways, that we're going to talk about. So with that, let's now turn the page.

Non-Receptor Protein Kinases

Okay. So, in this video, we're going to focus on the non-receptor protein kinases, specifically using the JAK-STAT pathway as an example. There are lots of words, but I am going to walk you through it. The JAK-STAT pathway is a pathway you are going to have to know about. You will read about it in your textbook, and you'll see it in the lecture because it's a great example of these non-receptor tyrosine kinases, which, other than briefly mentioning them previously, I haven't talked about at all. Because they're not a big class, but we do need to give you at least one example of them, and so this is it, the JAK-STAT pathway.

How this happens is there are these molecules called cytokines, and these are the ligands. Cytokines end up coming and binding to a cytokine receptor. I said that I was going to mention these receptors later, and so here is the short video on these receptors and this pathway. The ligands, called cytokines, come in and bind to the cytokine receptor on the plasma membrane. A kinase is recruited to the cytosol, and it has to be recruited. The kinase here is the Janus Kinase (JAK). This Janus Kinase gets brought to the receptor and activates the receptor once the ligand has been found.

Now, you have this complex of the receptor, the ligand, and JAK. What JAK does is it recruits a lot of different proteins, but the main one that we're going to talk about is STATs, and STATs are transcription factors. JAK recruits them; they phosphorylate and activate this family of transcription factors. Once STATs are activated, they then dissociate, travel to the nucleus, and affect gene expression.

Now, when I talk about the JAK-STAT pathway, you may think, oh, it's just JAK and just STAT. But it's actually not. These are families of proteins. There are actually 4 JAKs and 6 STATs, which can interact and regulate and work with different combinations to regulate different signaling pathways and different gene expressions. So, it's not just JAK and STAT; it's much more complex than that, with all these different combinations that it can form.

But, to just review this, what you see is you have your ligand, called a cytokine. It comes in and binds to the cytokine receptor. Once that happens, JAK is going to be recruited, and it's going to phosphorylate, because it's a kinase, and activate this receptor. Once that is active, STAT will actually be recruited here. And remember, STAT is going to be a transcription factor. So then, once they are activated, they think, "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. This is the main example for non-receptor tyrosine kinases because JAK is not a receptor but is the kinase. And also, the cytokine receptors that I said I was going to briefly mention later. So, with that, let's now turn the page.

Which of the following is not a common example of protein kinase signaling cascades?

• A. TGFβ
• B. Inositol Phospholipid pathway
• C. MAP Kinase pathway
• D. GTP signaling

Answer: (D)

Ligand binding to a receptor kinase causes what to happen?

• A. Immediate activation of the single receptor kinase
• B. Dimerization and inactivation of two receptor kinases
• C. Dimerization and activation of two receptor kinases
• D. Binding of the kinase to the receptor

Answer: (C)

Here’s what students ask on this topic:

What are protein kinase receptors and how do they function?

Protein kinase receptors are transmembrane proteins that play a crucial role in cellular signaling. They function by binding to specific ligands, which triggers their activation. This activation often involves dimerization (pairing of two receptor molecules) and transautophosphorylation, where one receptor phosphorylates the other. This phosphorylation creates docking sites for various intracellular signaling molecules, which then propagate the signal inside the cell. There are two main types: receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases, named based on the amino acids they phosphorylate. These receptors are essential for processes like cell growth, differentiation, and metabolism.

What is the RAS pathway and why is it important?

The RAS pathway is a critical signaling pathway activated by receptor tyrosine kinases (RTKs). RAS is a GTP-binding protein that acts as a major signaling hub. When activated, RAS switches from GDP-bound (inactive) to GTP-bound (active) state. This activation triggers a cascade of serine/threonine kinases, including the MAP kinase pathway, which ultimately regulates gene expression. The RAS pathway is significant because it is involved in cell growth and differentiation, and mutations in RAS are found in about 30% of all cancers, making it a key target for cancer research and therapy.

How is receptor activation inhibited in cells?

Receptor activation in cells can be inhibited through several mechanisms: 1) Receptor-mediated endocytosis, where the receptor is internalized and removed from the plasma membrane, preventing further signaling. 2) Lysosomal degradation, where the receptor is degraded if it is no longer needed. 3) Phosphotyrosine phosphatases, which remove phosphates from receptor tyrosine kinases, inactivating them. 4) SOCS proteins, which specifically inhibit cytokine receptors by terminating their signals. These mechanisms ensure that signaling is tightly regulated and does not persist longer than necessary.

What is the JAK-STAT pathway and how does it work?

The JAK-STAT pathway is a signaling mechanism involving non-receptor tyrosine kinases. It begins with cytokines binding to cytokine receptors on the cell membrane. This binding recruits Janus Kinases (JAKs) from the cytosol, which then phosphorylate and activate the receptor. Activated receptors recruit and phosphorylate STAT proteins (Signal Transducers and Activators of Transcription). Phosphorylated STATs dimerize and translocate to the nucleus, where they regulate gene expression. This pathway is crucial for processes like immune response and cell growth.

What are the main types of protein kinase receptors?

The main types of protein kinase receptors are receptor tyrosine kinases (RTKs) and receptor serine/threonine kinases. RTKs are the largest class and are activated by ligand binding, leading to dimerization and transautophosphorylation. This creates docking sites for intracellular signaling molecules. Receptor serine/threonine kinases, on the other hand, phosphorylate serine or threonine residues on target proteins. Both types play essential roles in cellular processes such as growth, differentiation, and metabolism.