Receptor Tyrosine Kinases - Online Tutor, Practice Problems & Exam Prep

Receptor Tyrosine Kinases (RTKs) are integral membrane proteins with an intracellular Tyrosine Kinase domain that phosphorylates tyrosine residues on target proteins. RTKs typically exist as monomers but dimerize upon ligand binding, leading to autophosphorylation and full activation. This activation allows RTKs to phosphorylate target proteins, initiating a cascade of cellular responses. Proteins with SH2 domains specifically bind to phosphorylated tyrosine residues, facilitating diverse cellular outcomes. Understanding RTK signaling is crucial for grasping cellular communication and response mechanisms.

Receptor Tyrosine Kinases

Alright. So here we're going to revisit our map of the lesson on biosignaling pathways, which is down below right here. And, of course, we know that we've been exploring this map by following the leftmost branches, and so we've already talked about G protein-coupled receptors or GPCRs in terms of the adenylate cyclase GPCR signaling pathway, the stimulatory pathway, including cAMP and PKA, as well as the inhibitory pathway including drugs and toxins affecting GPCR signaling, and then we also talked about phosphoenosetide GPCR signaling and all of these secondary messengers and enzymes down below. And so now that we've explored our G protein-coupled receptors branch to its entirety, we're now going to zoom out and start to explore a brand new branch on Receptor Tyrosine Kinases or RTKs. And so we'll get to introduce these right now. So let's get started.

Alright. So here we're going to introduce a different type of biosignaling receptor other than the GPCRs, and these are the Receptor Tyrosine Kinases. And so the Receptor Tyrosine Kinases, as you can see by these three bolded letters here, are commonly abbreviated as just RTKs. And so as you can see by their name, these Receptor Tyrosine Kinases are indeed receptor proteins themselves. And so this is a receptor protein, which means that it's going to be an integral membrane protein. But more specifically, the Receptor Tyrosine Kinases or RTKs are receptors with an intracellular Tyrosine Kinase domain. And so recall that the abbreviation, the 3 letter abbreviation for the amino acid residue Tyrosine is Tyr. And so we already briefly introduced Tyrosine Kinases in our previous lesson videos. And so recall that Tyrosine Kinases are Kinase Enzymes themselves, which means that these are enzymes that are going to phosphorylate, as their name indicates, Tyrosine residues on specific target proteins. And we'll talk more about this idea right here as we move forward in our course.

Now notice down below, we're going to introduce the 3 domains that are found in receptor Tyrosine Kinase or RTK monomers. And so notice that we have each of these 3 domains numbered right here and they're also color-coded to these monomers that you see over here in this part of our image. And so the very first domain is going to be an extracellular ligand binding domain. And so you can see that we have here this green shaded region is representing this first domain, the extracellular ligand binding domain. And it does exactly what it sounds like. It's going to be on the extracellular side or the outside of the plasma membrane, and it is going to bind to the ligand. And so you can see that the ligands here are shown in blue, and again, the extracellular ligand binding domains of these RTKs here are shown in green. And so, of course, the ligand is going to bind to the ligand binding domain. Now the next domain that we have here is a single transmembrane alpha helix. And so what you'll see is here, we have a single transmembrane alpha helix that is spanning the entire membrane, allowing this protein to be an integral membrane protein. And, over here we have another one as well. And so this represents one monomer and this represents another monomer over here. Now the 3rd and final domain in these RTK monomers are intracellular Tyrosine Kinase Domains. And so down here in purple, what we're showing you are these Tyrosine Kinase Domains, and so these, this portion of the receptor actually acts as an enzyme. They act as Tyrosine Kinases. And so this is important to keep in mind as we move forward in our course.

And so this here concludes our brief introduction to Receptor Tyrosine Kinases and we'll continue to learn more and more about these Receptor Tyrosine Kinases as we move along in our course. So I'll see you guys in our next video.

Receptor Tyrosine Kinases

Alright. So in this video, we're going to begin to introduce some of the functionality of receptor Tyrosine Kinases or RTKs. And by functionality, what we really mean is how exactly they work or operate within a cell. More specifically, we're going to introduce the dimerization and the autophosphorylation of these RTKs. It turns out that there are actually several different RTK classes that exist, and these RTK classes differ from each other in several different ways, including structurally. However, when you take a closer look at all of these RTK classes, they really do show that they can and usually exist as monomers or individual protein subunits. And again, this is how they usually exist because, in some cases, they do not exist as monomers and exist as dimers. We'll be able to see an example of RTKs that exist as dimers later in our course. But again, all I want you to know here is that they usually exist as monomers. However, although they usually exist as monomers, all RTK classes are always going to form some kind of dimer when they are activated. And of course, the dimer means that these 2 monomers are going to come together to form a complex. Notice down below that we have these 4 steps numbered 1 through 4 to show the dimerization and autophosphorylation of RTKs. And notice that the numbers that we have up above in our text actually correspond with the numbers that we have down below in our image. In the very first step of the dimerization and autophosphorylation of RTKs, what we have is just ligand binding, which pretty much is exactly what it sounds like. The ligand, which is again the extracellular primary messenger, is going to bind to the RTK. Notice what we're showing you is ligand binding. Notice that the ligand we're showing you is this diamond-shaped blue molecule, and notice that the receptor tyrosine kinases that we're showing you are separate individual monomers. We have one monomer circled in red over here and another monomer circled in red over here, and so these are separate individual RTK monomers, and each of them has their own extracellular ligand-binding domain here in green, so they can each bind their own ligand. That is it for step number 1. That leads us to step number 2. In step number 2, what we have is dimerization. Essentially, what we're going to see is that ligand binding to the RTK is going to cause a conformational change in the RTK. That conformational change is going to cause 2 RTK Monomers to actually dimerize with each other. And by dimerize, we mean is that they're going to come together and form a complex with each other. This dimerization step is going to occur only if it has not already dimerized. Later in our course, we're going to see an exception where the RTK already exists as a dimer. So if it already exists as a dimer, then you can pretty much think that step number 2 here is just going to be skipped. Depending on if the RTK is already dimerized or not, then the ligand binding and or the RTK dimerization is going to lead to partial activation. It's going to partially activate both Tyrosine Kinase domains on both receptor tyrosine kinase monomers. Notice that we're showing you the dimerization of the receptor Tyrosine Kinases. Notice that we're showing you here with these arrows the movement of these 2 RTK Monomers together forming a dimer. Notice that upon dimerization, they're much closer together and forming a complex with each other now, that it actually leads to partial activation of the receptor Tyrosine Kinase, Kinase domains, which are these intracellular purple domains that you see down below. What you'll notice is that within these domains that you'll see these Ys here and recall that the Y is the one-letter amino acid code for Tyrosine amino acid residues. So you can see that we're just labeling some Tyrosine amino acid residues here in these Tyrosine Kinase domains. After dimerization is complete, and we have partial activation of the Tyrosine Kinase domains, That leads us to step number 3. In step number 3, what we have is the autophosphorylation of the RTKs. Autophosphorylation really just means self-phosphorylation. When a protein phosphorylates itself or when protein dimers are phosphorylating each other. The monomers within the dimer are phosphorylating each other. In this step of autophosphorylation, what we'll see is that the partially activated Tyrosine Kinase domains, again, this partial activation is going to allow the Tyrosine Kinase domains to autophosphorylate each other or to cross phosphorylate each other. Here, we could also put the word cross phosphorylate. We'll be able to see that down below in our image, and, of course, this cross-phosphorylation, this autophosphorylation leads to the full activation of the Tyrosine Kinase domains. Notice that we're showing you the autophosphorylation of these Tyrosine Kinase domains. Notice that, again, partial activation in the previous step is going to allow these 2 domains to phosphorylate each other, to cross-phosphorylate each other in a process known as autophosphorylation. They are Tyrosine Kinase domains, so they phosphorylate specifically the Tyrosine residues on the opposite monomer. The autophosphorylation of these domains actually leads to the full activation of these Tyrosine Kinase domains, and that leads us to our step number 4. So in our final step, step number 4, what we have is the RTK will phosphorylate its targets. And so the autophosphorylated RTK, now that it is fully activated, it can now phosphorylate other target proteins. This is ultimately going to lead to a cascade of phosphorylation, and the cascade of phosphorylation results in changes to metabolism and gene expression, which ultimately leads to the cell response that's associated with the bio signaling involving these receptor Tyrosine Kinases. If we take a look at our step number 4 down below over here, notice that we are showing you the RTK target phosphorylation. So now that we have a fully activated autophosphorylated Tyrosine Kinase domains, they can now phosphorylate other target proteins, such as this target protein here, and phosphorylate them to alter their activity. The alteration in their activity ultimately will lead to the cell response that's associated with RTK bio signaling. As we move forward in our course, we'll be able to see more specific target proteins and we'll be able to talk a lot more about very specific receptor tyrosine kinase biosignaling pathways. But for now, this here concludes our introduction to the dimerization and the autophosphorylation of receptor tyrosine kinases. As we move forward in our course, we'll be able to get some practice applying some of these concepts. So I'll see you guys in our next video.

Which of the following statements is NOT true of receptor tyrosine kinases?

• A. Monomeric receptors are often induced to dimerize upon ligand binding.
• B. The activated receptors attract and activate G proteins to continue the GPCR signaling pathway.
• C. The cytoplasmic side of RTKs contains a kinase enzyme domain that is partially activated upon ligand binding.
• D. Activated RTKs autophosphorylate themselves and can attract proteins with SH2 domains.

Receptor Tyrosine Kinases

So in this video, we're going to introduce how some proteins with SH₂ domains are capable of binding to phosphorylated tyrosine residues, which really makes these SH₂ domains super relevant to receptor Tyrosine Kinases. And so here's what you guys need to know. Some proteins have what's known as a src homology 2 domain or as you can see by the bolded letters right here, an SH₂ domain for short. And so these particular proteins that have an SH₂ domain are capable of directly binding to phosphorylated Tyrosine Residues. Now what's really important for you guys to note is that proteins that have these SH₂ domains do not bind to phosphorylated serine or threonine residues. Again, these proteins that have SH₂ domains can only bind to phosphorylated tyrosine residues, which is again what makes these SH₂ domains so relevant to receptor Tyrosine Kinases. Now the SH₂ domains of these proteins can either bind directly to, number 1, autophosphorylated RTKs, or they can bind directly to, number 2, phosphorylated target proteins of the RTKs. And so notice that number 1 and number 2 here in the text corresponds with the number 1 and the number 2 that you see down below in our images. And so if we take a look at this image over here on the left-hand side for number 1, notice that we have a ligand-bound and dimerized and autophosphorylated receptor tyrosine kinase here in the membrane. And notice that we also have this blue protein over here, and this blue protein notice has an SH₂ domain. And again, the SH₂ domain allows it to bind phosphorylated Tyrosine Residues. And again, Y is the one-letter amino acid code for Tyrosine. And so you can see we have a phosphorylated Tyrosine and the SH₂ domain is bound to that phosphorylated Tyrosine. And more specifically, the SH₂ domain of this blue protein right here is bound directly, as we indicated above, bound directly to the autophosphorylated receptor Tyrosine Kinase. And so, notice down below what we're saying is that in some cases the SH₂ domains of some proteins will bind directly to the RTK or binds to RTKs directly. And so you can see that when the protein, the blue protein's SH₂ domain binds to the phosphorylated tyrosine residue that can actually activate this protein and this activated protein can ultimately generate the cell response that we're calling cell response number 1 here generically. But as we move forward in our course, we'll be able to see an example of this, in more detail. But notice over here in the image on the right-hand side, again, once again we have our ligand-bound and dimerized and autophosphorylated protein here. And because these are phosphorylating its target protein here, and because these are Tyrosine Kinase Domains, we know that the target protein is phosphorylated at a Tyrosine Residue. And so notice that this yellow protein over here also has an SH₂ domain, just like this protein over here has an SH₂ domain. But notice that this SH₂ domain over here on the yellow protein is not bound directly to the receptor Tyrosine Kinase like it was over here. Instead, this SH₂ domain of the yellow protein is bound to the phosphorylated tyrosine residue on the target protein of the RTK. As we indicated above that these SH₂ domains can bind directly to the phosphorylated target proteins of the RTKs. And so, again, when the SH₂ domain of this protein binds to its phosphorylated tyrosine residue, it can activate this protein and that activated protein can lead to the cell response that we're calling cell response number 2. And so this binding of the SH₂ domain can lead to a different cell response potentially than if the SH₂ domain binds directly to the And so notice down below in our text here, what we're saying is that the SH₂ domains of some proteins are capable And so, one thing that's also very important to note here is that proteins that have SH₂ domains can have a wide variety of functions. And so because this protein with an SH₂ domain can have a different function, then this protein over here, which also has an SH₂ domain, this is what allows receptor tyrosine kinases to elicit a wide variety of cell responses through their bio signaling. And And so again, we'll be able to see examples of more specific RTK bio signaling pathways as we move forward in our course. But for now, this here concludes our introduction to how some proteins with SH₂ domains are capable of binding to phosphorylated Tyrosine Residues. And so, we'll be able to get some practice applying the concepts that we've learned as we move forward in our course. So I'll see you guys in our next video.

Proteins that contain a src homology 2 domain (SH2 domain):

• A. Have a phosphoserine residue that causes them to bind to other proteins.
• B. Have a phosphotyrosine residue that causes them to bind to other proteins.
• C. Bind to any proteins that have a phosphothreonine group.
• D. Bind to proteins that have a phosphotyrosine residue and a specific conformation.
• E. Binds to proteins that have 2 sulfhydryl groups.

Here’s what students ask on this topic:

What are Receptor Tyrosine Kinases (RTKs) and how do they function?

Receptor Tyrosine Kinases (RTKs) are integral membrane proteins with an intracellular tyrosine kinase domain. They function by binding to extracellular ligands, which causes the RTKs to dimerize. This dimerization leads to autophosphorylation, where the tyrosine residues on the RTKs phosphorylate each other. This phosphorylation fully activates the RTKs, allowing them to phosphorylate target proteins. This initiates a cascade of cellular responses, including changes in metabolism and gene expression. RTKs play a crucial role in cellular communication and response mechanisms, making them essential for understanding biosignaling pathways.

What is the significance of dimerization and autophosphorylation in RTKs?

Dimerization and autophosphorylation are critical steps in the activation of Receptor Tyrosine Kinases (RTKs). Upon ligand binding, RTKs dimerize, meaning two monomers come together to form a complex. This dimerization causes a conformational change that partially activates the tyrosine kinase domains. These partially activated domains then autophosphorylate, or cross-phosphorylate, each other, leading to full activation. This full activation allows RTKs to phosphorylate other target proteins, triggering a cascade of cellular responses. These processes are essential for the proper functioning of RTK-mediated signaling pathways.

How do SH2 domains interact with phosphorylated tyrosine residues in RTK signaling?

SH2 (Src Homology 2) domains are protein domains that specifically bind to phosphorylated tyrosine residues. In RTK signaling, proteins with SH2 domains can bind to phosphorylated tyrosine residues on autophosphorylated RTKs or on phosphorylated target proteins of RTKs. This binding is highly specific and does not occur with phosphorylated serine or threonine residues. The interaction between SH2 domains and phosphorylated tyrosine residues facilitates the activation of downstream signaling proteins, leading to diverse cellular responses. This specificity and versatility make SH2 domains crucial for the propagation of RTK signaling pathways.

What are the three main domains of Receptor Tyrosine Kinases (RTKs)?

Receptor Tyrosine Kinases (RTKs) have three main domains: 1) an extracellular ligand-binding domain, 2) a single transmembrane alpha helix, and 3) an intracellular tyrosine kinase domain. The extracellular ligand-binding domain is responsible for binding to specific ligands outside the cell. The single transmembrane alpha helix spans the cell membrane, anchoring the RTK in place. The intracellular tyrosine kinase domain functions as an enzyme that phosphorylates tyrosine residues on target proteins. These domains work together to transmit signals from the extracellular environment to the cell's interior, initiating various cellular responses.

What role do RTKs play in cellular communication and response mechanisms?

Receptor Tyrosine Kinases (RTKs) play a pivotal role in cellular communication and response mechanisms. They act as receptors for extracellular ligands, such as growth factors, hormones, and cytokines. Upon ligand binding, RTKs dimerize and autophosphorylate, leading to the activation of their intracellular tyrosine kinase domains. This activation triggers a cascade of phosphorylation events, ultimately resulting in changes in cellular activities such as metabolism, gene expression, and cell division. RTKs are crucial for processes like cell growth, differentiation, and survival, making them essential for maintaining cellular homeostasis and responding to external signals.