Insulin Signaling as a Growth Factor - Online Tutor, Practice Problems & Exam Prep

Insulin signaling as a growth factor involves the activation of receptor tyrosine kinases (RTKs) and the subsequent RAS and MAPK pathways. Initially, insulin binds to its receptor, activating IRS-1, which then interacts with GRB2 and SOS, leading to RAS activation. RAS, a monomeric G protein, activates RAF1 (MAPKKK), which phosphorylates MEK (MAPKK), activating ERK (MAPK). ERK enters the nucleus to regulate transcription factors that promote cell growth. Termination of this signaling involves RAS's GTPase activity and phosphatases that reverse phosphorylation, resetting the pathway.

Insulin Signaling as a Growth Factor

Alright. So here we're going to briefly revisit our map of the lesson on biosignalling pathways, which is down below right here. And, of course, we know that we've been exploring this map by following the leftmost branches first. And so already in our previous lesson videos, we've covered g protein coupled receptors or GPCRs, as well as all of these specific GPCR signaling pathways down below. And so recently, we've been exploring a new branch here for receptor Tyrosine Kinases or RTKs, and we've introduced insulin and the insulin receptor, which is an RTK. We talked about a very specific insulin RTK signaling pathway on glucose metabolism, which included the enzymes PI3K, the substrate PIP₃, and the enzymes PKB and PDK1. And so here in this video, we're going to begin a new insulin RTK signaling pathway where insulin, instead of affecting glucose metabolism, is actually going to act as a growth factor. And so insulin RTK signaling as a growth factor includes two main pathways that are embedded within this, and these pathways are the RAS pathway and the MAPK pathway. Now, the RAS pathway includes components GRB2, SOS, and RAS, of course. And the MAPK pathway includes the components RAF1, MEK, and ERK. And so moving forward in our course, we're going to discuss, again, the insulin RTK signaling pathway as a growth factor, and then we'll start with the RAS pathway, which includes these components, and then later, we'll follow up with the MAPK pathway. And so let's go ahead and get started talking about this.

Alright. So here we're going to begin our introduction to insulin signaling as a growth factor. And so recall that in our previous lesson videos when we introduced insulin, we said that one of insulin's primary biological effects was to decrease blood glucose concentration by regulating glucose metabolism. But also recall that in our previous lesson videos, we said that in addition to regulating glucose metabolism, insulin would also stimulate cell growth by regulating gene expression. And so insulin can also act as a growth factor. Now insulin growth factor RTK signaling is actually triggered by the following pathway that you see right here, GRB2, followed by SOS, followed by RAS, followed by the MAPK pathway. And so in our next lesson video, we're going to introduce these exact components that you see here. And then later, we'll talk more about the MAPK pathway. But for now, this here concludes our introduction, and I'll see you guys in our next lesson video where we talk about the RAS pathway. So see you guys there.

Insulin Signaling as a Growth Factor

So here we're going to begin our lesson on Insulin Growth Factor Signaling via the RAS pathway, and we'll introduce what this RAS pathway is here very shortly. Now first, we need to recall from our previous lesson videos that insulin results in an active and phosphorylated Insulin Receptor Substrate 1 or IRS 1. And so just as a reminder, notice over here on the left-hand side of our image, we're showing you the 51 amino acid peptide hormone, insulin, binding to the insulin receptor. When insulin binds to the insulin receptor, it activates the autophosphorylation of the beta domains. These beta domains are Tyrosine Kinase domains, and they phosphorylate Tyrosine residues on each other. That fully activates the Tyrosine Kinase domains here so that it can phosphorylate its substrate, insulin receptor substrate 1 or IRS 1, which leads to again an active and phosphorylated IRS 1 protein. This is a reminder from our previous lesson videos. We already knew that insulin would lead to active IRS 1. This is again a recall from our previous lesson videos that insulin results in active IRS 1. And really, this is exactly where we pick up with when we start the RAS pathway. We start the RAS pathway with an active IRS 1. Even though we're starting the RAS pathway with active IRS 1, we still can't forget the previous steps here of the RTK, the insulin binding, the autophosphorylation, and again the phosphorylation of IRS into IRS 1. This is just a reminder again from our previous lesson videos.

Now also recall from our previous lesson videos that active IRS one really acts as a branch point in insulin biosignaling. It can lead to many different pathways. You might recall in our previous lesson videos, we saw active IRS 1 in insulin signaling on glucose metabolism. Here we're going to see active IRS 1 once again, but this time it's not going to be involved in glucose metabolism. It's going to be involved in growth factor signaling. Again, IRS 1 can act as a branch point in insulin biosignaling and can lead to many different pathways, including this RAS pathway that we're about to introduce here.

So what is this RAS here that the RAS pathway is referring to? Well, Ras is actually a lipid linked monomeric g protein. But wait a second, I thought you said that g proteins were involved with GPCRs, g protein coupled receptors. Not with RTKs like the insulin receptor that we have below. It turns out that the Ras g protein is an exception to this. Ras is a G Protein that is not involved with GPCRs; instead, it's involved with the Insulin RTK, a receptor tyrosine kinase. Another difference is in our previous lesson videos with the GPCRs, the g proteins were heterotrimeric g proteins, meaning that they had 3 different subunits, the alpha, beta, and gamma subunits. But notice that this g protein here in Ras is not a heterotrimeric g protein. Instead, it's a monomeric g protein, meaning that it only has one single subunit instead of 3 different subunits. This Ras g protein, monomeric g protein, exists in two forms as you might expect. It exists in a GDP bound form, which is the inactive form, and it also exists in a GTP bound form, which is the active form. This is important to keep in mind as we move along and talk more about this RAS pathway.

Really the ras pathway is a 3 step cascade of protein interactions, and these three steps really lead to the activation of this rasg protein during insulin signaling as a growth factor. Notice down below, we have each of the 3 steps in this cascade numbered in our text, and of course, the numbers that you see here in our text correspond with the numbers that you see below in our image. In the very first step of this RAS pathway, pathway, again, we're starting with active IRS 1, and so we're starting right here at this portion of our image. The active IRS 1 is going to serve as a binding site, as an adapter protein for the SH2 domain of the adapter protein called GRB2. If we take a look at our image below, notice that IRS 1 over here is acting as an adapter protein, and the SH2 domain of this protein right here, which is GRB2, is binding to the phosphorylated tyrosine residue on IRS 1, and this is going to activate GRB2, which is another adapter protein. As we indicated above, GRB2 is an adapter protein. This leads us to step number 2, and that is that GRB2's SH3 domain, which is on the opposite side of the protein, is going to serve as a binding site for another protein called SARS. When it binds to GRB2, it's going to form an IRS 1, GRB2 SARS complex since they're all binding to one another. If we take a look at our step number 2 below, notice that the SH2 domain of GRB2 is binding to IRS 1. However, on the opposite end, we have an SH3 domain on GRB2 that is binding to this other orange protein over here that we're calling SARS. Now what we have is an IRS 1, GRB2, and SARS complex after step number 2, as we indicated above.

So then that leads us to step number 3, and what's important to note is that the bound SARS protein is actually a guanine exchange factor, which you can see by these bolded letters here is abbreviated as a GEF or Gef protein. The sauce, because it is a guanine exchange factor, is going to allow for the guanine exchange in our g protein. It's going to catalyze the replacement of GDP, the low energy inactive form, with GTP, the high energy active form, on our ras monomeric g protein. Notice below in our image in step number 3 right here that we have this green protein right here, which is a monomeric g protein called Ras. Ras is in its inactive state right here originally, where it is bound to GDP. But when SARS is bound to GRB2 and SARS becomes activated, SARS can then act as the guanine exchange factor that it is or the Geth that it is, it's going to catalyze the replacement of GDP with GTP to activate RAS. You can see that we have GTP replacing GDP here in the ras protein. And of course, here we have the ras bound to GTP, which is the active form of our ras monomeric g protein. This active ras will actually regulate cell growth via activation of another signaling pathway called the mapk signaling cascade or the mapk signaling pathway. Notice that here we're showing how RAS, the active form of RAS, will activate another pathway called the map K signal cascade. We'll talk about this map K signal cascade in our next lesson video. But for now, this here actually concludes the ras pathway. The ras pathway ends with an active rasg protein.

Now what's also important to note here is that very similar pathways to the one that we just discussed above where IRS 1 activates GRB 2, activating SARS, activating RAS. Very similar pathways can also be initiated by other signaling molecules other than insulin. So they can be initiated by a variety of other growth factors, such as for example, EGF, or epidermal growth factor, or PDGF, or platelet-derived growth factor. Here we have these abbreviations for you. You may see in some of your textbooks that insulin does not act as the ligand for this pathway, but instead, perhaps it is again epidermal growth factor or EGF or perhaps even PDGF, platelet-derived growth factor, which again can stimulate very similar pathways to the one that we discussed above. But this here concludes our introduction to the insulin growth factor signaling via the RAS pathway and we'll be able to get some practice applying this as we move along. And of course, later we'll continue to talk about the mat K signaling cascade as well. So I'll see you guys in our next video.

Insulin Signaling as a Growth Factor Example 1

Alright. So here we have an example problem that wants us to complete the sentence here using one of these four potential answer options down below. It states that G proteins such as Ras are activated when, and of course, what we need to recall from our previous lesson videos is that Ras is a monomeric G protein, and it is an exception to other G proteins that are involved with G Protein Coupled Receptors or GPCRs. Because Ras is not involved with GPCRs. Instead, it's going to be involved in insulin RTK signaling pathways as a growth hormone. And so Ras, although it is found in these RTK pathways, it's actually going to keep that same feature of activation as the other G proteins. And so, of course, what that means is that the activated Ras is going to be active when it's bound to the GTP molecule. And so we can say that when it's bound to GTP, that's when G proteins such as Ras are active. And so we can go ahead and indicate that b here is the correct answer. Option a is incorrect because it states bound to GDP, but this is the low energy inactive form. And when Ras is bound to GDP, it would be inactive just as we might expect with our other G proteins as well. And then, of course, we did not talk about Ras getting phosphorylated at any point and so those two answers are incorrect. And again, option b here is the correct answer. So that concludes this practice and I'll see you guys in our next video.

In the insulin signaling pathway to activate the protein Ras, activated IRS-1 binds to ___________.

• A. Adenylate cyclase.
• B. SH2 domain of Grb2.
• C. PLC.
• D. GTP-bound Ras.
• E. Insulin.

Insulin Signaling as a Growth Factor

So in our last lesson video, we said that the Ras pathway ends with an activated monomeric RasG protein that ends up activating another pathway called the MAPK signaling cascade. And so here in this video, we're going to introduce what MAPK is. And so MAPK is really just an abbreviation for Mitogen Activated Protein Kinases, as you can see by the first letter of each of these words giving us MAPK. As you can see by the name, these are indeed kinases themselves, and so they are going to be enzymes that phosphorylate their substrates. But more specifically, these Mitogen Activated Protein Kinases or MAPKs are enzymes that phosphorylate their substrates and lead to cell growth. And so what can remind us that these MAPKs lead to cell growth is the word mitogen itself. Mitogens are really just a specific type of growth factor that specifically induce mitosis and cell division, leading to cell growth. Now what's really important to note about these MAPKs is that these MAPK enzymes can actually be regulated and phosphorylated by other MAPK enzymes. And so if we take a look at our example image down below of MAP Kinase MAPK Kinases, we will be able to understand this regulation in phosphorylation by other MAPKs. And so let's say down below here in this green circle, this represents our Mitogen Activated Protein Kinase, our MAPK. And let's say that this MAPK, because it is a kinase, it's going to go on to phosphorylate other substrates. But if this MAPK is regulated by phosphorylation by another kinase, then this kinase right here in red would be referred to as a MAPKK because this is a kinase that phosphorylates the enzyme MAPK. And so more specifically, we could refer to this enzyme right here as a MAPKK, because it is a kinase that phosphorylates MAP Kinase or MAPK. And if this enzyme right here is phosphorylated and regulated by phosphorylation by another kinase up here, then this would be referred to as the MAPKKK, because this is a kinase that regulates MAPKK. And so then this protein up here could be referred to as the MAPKKK, and so what you end up getting is the MAPKK regulates MAPKK, and MAPK regulates MAPK, and MAPK goes on to phosphorylate the downstream targets that leads to mitosis and cell division. And so as we move forward in our course, we're going to see some specific examples of MAPKKKs, MAPKKs, and MAPKs as well. So keep this regulation here in mind. And so this here concludes our brief introduction to MAPKs. And in our next lesson video, we'll be able to continue our lesson on the MAPK signaling cascade. So I'll see you guys there.

Insulin Signaling as a Growth Factor

So here we're going to discuss how the RAS pathway that we covered in our previous lesson videos activates the MAPK signaling pathway. Recall from our previous lesson videos that the RAS pathway results in an active GTP-bound RAS protein that initiates another four-step MAPK signaling cascade. Notice down below, we're showing you each of the four steps in the MAPK signaling cascade as a continuation of the three steps from the RAS pathway that we covered in our previous lesson videos. If we take a look at our image down below on the left-hand side, notice that we're pretty much showing you the same image from our previous lesson videos of the RAS pathway. Notice that the first three steps here, step 1, step 2, and step 3, are shaded in gray because, again, these are the steps that we already covered in our previous lesson videos of the RAS pathway. The new steps that we're introducing here in this video are steps 4, 5, 6, and 7, which are really the four steps of the MAPK signaling cascade that we're introducing here in this video. So these steps, 4, 5, 6, and 7, correspond with the numbers above in our text.

The very first step of the MAPK signaling cascade, which corresponds with step 4 here, is the active RAS GTP from our RAS pathway, which is going to directly activate a MAPKKK, a kinase that regulates a MAPKK via phosphorylation. This MAPKKK here is actually the protein called RAF1. If we take a look at our image down below at step number 4, notice that step number 4 is starting with the active RAS GTP protein, the end result of the RAS pathway. This active RAS GTP protein is associating itself with this other protein called RAF1, and RAF1 is our MAPKKK. This is it for our step number 4, leading us directly into step number 5.

In step number 5, the activated RAF1 protein, this MAPKKK, is going to phosphorylate two serine residues on a MAPKK called MEK, which is going to activate MEK. If we take a look at our image down below in step number 5, notice that RAF1, the MAPKKK, is regulating another MAPKK via phosphorylation and this MAPKK is MEK. When MEK is not phosphorylated, it is in its inactive state. But as soon as RAF1 phosphorylates MEK on these two serine residues, MEK becomes active. MEK is a kinase itself, leading us directly into step number 6.

In step number 6, the active MEK is going to phosphorylate the serine and tyrosine on a MAPK called ERK, activating the MAPK called ERK. If we take a look at our step number 6 down below, notice that here what we have is our MAPK called ERK. When ERK is not phosphorylated, it is inactive; however, upon being phosphorylated by the MAPKK, MEK, it becomes active. ERK represents our MAPK, so we can label this as our MAPK right here. This leads us directly into step 7.

In step number 7, as you can see in our text above, the active ERK protein is going to enter into the nucleus of the cell and regulate the activity of transcription factors. These transcription factors that it regulates are specifically related to cell growth here in this insulin signaling pathway as a growth hormone. Transcription factors are proteins that induce the process of transcription, which is when DNA is transcribed into RNA. Transcription factors will induce transcription of very specific target genes, which again are going to be related to cell growth here in this pathway. In terms of the specific transcription factors that are affected by ERK, ERK actually regulates many different types of transcription factors, including the transcription factors called ALK1, SERF, JUNE, FOSS, and MYC, and probably much more than that as well. The exact transcription factors that you are responsible for knowing in this pathway will depend on your professors. Over here, what we have is this little hand symbol to remind you guys that you should raise your hand in class and ask your professor exactly which transcription factors you are responsible for knowing in this pathway. If we look at our step number 7 down below in our image, notice that the activated ERK protein, which is our MAPK, in step number 7, is going to enter into the nucleus of the cell, which we have over here in this corner, and regulate the activity of transcription factors related to cell growth. This is showing the entire pathway, the insulin RTK signaling pathway as a growth factor. Ultimately, what you see is that insulin binding can lead to transcription factor regulation of cell growth. The InsulinRTK signaling pathway, as a growth factor, includes the RAS pathway, which are steps 1, 2, and 3 here, as well as the MAPK pathway, which are steps 4, 5, 6, and 7. This here concludes our video on the introduction to how the RAS pathway activates the MAPK signaling pathway, and as we move forward in our course, we'll be able to apply the concepts that we've learned. I'll see you guys in our next video.

Insulin Signaling as a Growth Factor Example 2

Alright. So here we have an example problem that says all of the following are true in the RAS and MAPK pathways, except for which one of these 4 potential answer options down below. And of course, because we're looking for the exception here, really we're looking for the false answer option. And so option a here says that GRB2 changes conformation and binds to the next protein SOS in the signal transduction pathway. And so recall from our previous lesson videos where we covered the RAS pathway that option a here is actually a true statement. And so after GRB2 binds to IRS1, it's going to activate it and change its conformation so that it can bind to the next protein SOS. And so, this is a true statement, so it's not the false exception that we're looking for, and we can eliminate answer option a.

Now answer option b says SOS acts as a GAP in the activation of the protein RAS, but maybe you don't remember us mentioning anything about GAP here. So let's skip this one for now, and we'll come back to it a little bit later. Let's check option c. So c says RAS exchanges GDP for GTP and activates RAF1, which is the first kinase in the MAPK pathway. And so again, if you recall from our previous lesson videos where we covered the MAPK pathway, that, this is actually a true statement. And so RAS, we know, is a monomeric G protein, and the way that it becomes activated is by exchanging its low energy GDP for its high energy GTP. And the first thing that RAS does when it becomes activated is it activates another MAPKKK called RAF1. And this is the first kinase in the MAPK pathway. So this is a true statement, and we can eliminate answer option c because it's not the false exception that we're looking for.

And so, moving on to option d here, it says the MAPK pathway regulates transcription factors that regulate specific genes. And you might recall that this is also a true statement, and the reason that it's true is because recall that the MAPK pathway ends with the activation of the MAPK called ERK, and ERK makes its way into the nucleus to regulate transcription factors that regulate specific genes. So, again, we can eliminate answer option d because it's not the false exception that we're looking for.

And so that must mean that option b here is the false exception that we are looking for. But what is false about option b? Didn't we say that SOS was used to activate the protein RAS? Well, that part of this answer is actually true. SOS is used to activate the protein RAS. However, SOS does not act as a GAP, and we have not yet talked about GAPs yet here in our course, but we will in our next lesson video. But SOS actually does not act as a GAP. Instead, it acts as a GEF, a guanine exchange factor. And so the GAP part is really what makes answer option b the false answer option that we were looking for. And so because answer option b is the false exception that we were looking for, we can go ahead and mark this as the answer we were looking for. And that concludes this practice or this example problem, and I'll see you guys in our next video.

Insulin Signaling as a Growth Factor

So here in this video, we're going to discuss the termination of insulin signaling as a growth factor. Now just like all of the other G proteins that we talked about in our previous lesson videos, the monomeric G Protein Ras also possesses GTPase activity. Now recall that the GTPase activity is really just referring to the ability of these G proteins to cleave or hydrolyze the high energy and active GTP into the low energy and inactive GDP. And so really, Ras's GTPase activity is serving to terminate the signal and to help reset the pathway back to the inactive state. Now what's really important to note about Ras's GTPase activity is that Ras's GTPase activity is actually very, very slow. So slow that it's actually not going to occur at a reasonable rate on its own. However, Ras's GTPase activity can actually be sped up with the help from other proteins. And so these other proteins that help to speed up Ras's GTPase activity are called GTPase activating proteins or GAP for short or just GAP proteins. And so these GTPase activating proteins or GAPS as their name implies are just proteins that are going to activate the GTPase activity of Ras. And so they're going to increase the rate of Ras's GTP hydrolysis, which of course we mentioned up above is going to thus inactivate Ras. And so notice that this dotted box that we have up above in our text corresponds with the dotted box that we have down below in our image, which is showing Ras's GTPase activity. And so notice over here on the right, what we have is the active Ras, which is bound to the high energy and active GTP. And notice that the arrow pointing to the left is showing the reaction that inactivates Ras, where it's going to hydrolyze the high energy and active GTP into the low energy and inactive GDP. But again, Ras's GTPase activity is really, really slow, so it can only really occur with the help of other proteins called GAP proteins. And so here in this blank, we can fill in the gap and write in GAP for these GAP proteins. And so the GAP proteins are going to help accelerate Ras's GTPase activity where it will again cleave off one of the phosphate groups and form the low energy and inactive GDP. And of course, once Ras is inactive, that's going to help, again, terminate the insulin signal as a growth factor. Now what's also important to note is we've got all these red arrows down below in our image, and all of these red arrows are really just referring to phosphatases, which recall are enzymes that remove phosphate groups and thus will reverse the kinase activity in this pathway. And so we know that the insulin signaling as a growth factor includes, the activity of a lot of different kinases that phosphorylate things. And so phosphatases are going to be really important to remove all of those phosphate groups, reverse the kinase activity and help to reset the pathway, back to the beginning. And so if we take a look at our image down below, notice that we have all of these red arrows and the red arrows are showing the phosphatase activity, which removes the phosphate groups from all of these proteins and changes them to their inactive state. So you can see MEK here is being, the phosphatase activity is acting on MEK which is removing its phosphatase, its phosphate groups. And even IRS 1 phosphate groups can be removed by phosphatases and even the phosphate groups on the tyrosine kinase domains can be removed as well. And so essentially, the main takeaway here of this video is that the removal of phosphate groups by phosphatases and by Ras' GTPase activity here when it cleaves GTP into GDP are really going to help terminate the signal and help reset the entire pathway. And so this here really concludes our lesson on the termination of insulin signaling as a growth factor. And as we move forward in our course, we'll be able to get some practice applying these concepts. So I'll see you guys in our next video.

The monomeric G-protein Ras is activated by _______________, while _______________ helps turn Ras off.

• A. Grb2 ; MAPK.
• B. Sos ; GAP.
• C. IRS-1 ; GAP.
• D. MAPK ; Raf-1.
• E. GAP ; Sos.
• F. GEF ; Sos.

Insulin Signaling as a Growth Factor

So, as you guys have probably noticed from our previous lesson videos, when it comes to insulin signaling as a growth factor, there's a lot for you guys to remember. And so, how in the world are you guys supposed to remember the most important components in the correct order when it comes to insulin RTK signaling as a growth factor. Well, that's exactly what this video is all about right here, and I'm going to share with you guys a really creative and unique story that you'll only find here at Clutch Prep that's designed intentionally to help you guys remember the most important components and in the correct order for insulin RTK signaling as a growth factor.

And so, what you'll notice is over here on the right-hand side, we have this image that shows you the most important components in the correct order for insulin RTK signaling as a growth factor. And so, notice the top part up here represents the RAS pathway, and notice that it ends with Ras. And then of course the bottom pathway down here represents the MAPK pathway. And so, both the RAS pathway and the MAPK pathway are involved in insulin RTK signaling as a growth factor. And so, notice over here on the left-hand side, we're showing you the 7 steps to this story. And these 7 steps that you see here correspond with the 7 steps from our previous lesson videos for insulin RTK signaling as a growth factor. And also, these 7 steps also correspond with the seven numbers that we have down below in our image, and so that's important to keep in mind as we move forward.

Now, this story is not fully bulletproof. It's not a perfect story to help you memorize all of the different details. Again, it's only designed to help you guys memorize the most important components in the correct order. So, because this pathway starts off with activated IRS 1, the first step of our story is that the IRS, the Internal Revenue Service, gives another tax refund. And again, that represents IRS 1. So, if we take a look at our image down below, notice that step 1, again, is this cash influx or this tax refund that the IRS is providing. And so that leads us to our second step, and that is that the cell decides to use that money, that tax refund money, to buy 2 orders of wings on Grubhub. And so, the two orders on Grubhub represent GRB 2, the adapter protein that binds to IRS 1.

And so, when that Grubhub food actually arrives, the cell decides to add some sauce, some hot sauce to it, and that reminds us of the sauce, guanine exchange factor. And after the cell adds some hot sauce, he starts eating the food and all of a sudden the hot sauce starts to activate a rash, and the rash, of course, represents the monomeric RAS G protein. And so, if you take a look down below in our image, step number 4, he's saying, I got a rash from eating those chicken wings there.

In step number 5, the cell decides to call Dr. Raphael, and Dr. Raphael represents the MAPKKK called RAF 1. And if you look down below, you can see that we've got Dr. Raf here on the phone since the cell's giving him a call. Doctor Raf says he's going to make the irking pain go away, and the irking pain here represents the MAPK ERK. And so, you can see down below that Dr. Raf tells the cell that he's going to make the irking pain go away. You can see we've got this ERK pill here for step number 7. And, of course, the ERK pill is going to make its way into the nucleus, and so, you can see the guy's mouth over here represents the nucleus.

It's a really silly, really crazy story, but it can be really helpful for memorizing the most important components of this pathway in the correct order. And so, by practicing this story just a handful of times you guys will get this down, no problem. And so, this here concludes our lesson on how to remember the insulin RTK signaling as a growth factor, and we'll be able to get some practice in our next couple of videos. So, I'll see you guys there.

Place the insulin RTK signaling events in order from 1-7:

a) Ligand binding results in autophosphorylation of the receptor tyrosine kinase ______.

b) MAPKK (Mek) phosphorylates MAPK (Erk) ______.

c) Sos binds then activates Ras ______.

d) Receptor tyrosine kinase phosphorylate IRS-1, which binds the SH2 domain of Grb2 ______.

e) Ras activates MAPKKK (Raf-1) ______.

f) MAPK (Erk) activates transcription factors to regulate mRNA synthesis ______.

g) MAPKKK (Raf-1) phosphorylates MAPKK (Mek) _______.

Alright. So this practice problem wants us to place the insulin RTK signaling events in order from 1 to 7. And so notice down below we have these 7 different events. And over here on the right, we have these blanks where we can put in the numbers to order each of these events. And so after reading each of these events, of course, the very first event is going to be ligand binding. And so we know that the ligand in this scenario is going to be insulin, and it will bind the receptor, and that's going to result in the autophosphorylation of Tyrosine Kinase or the RTK. This will be the very first event. And then of course, the autophosphorylation of the RTK leads to the full activation of the RTK. And so the RTK or the receptor tyrosine kinase will be able to phosphorylate its substrate, which is the insulin receptor substrate 1 or IRS1, which will then bind the SH2 domain of the adapter protein GRB2. And so of course, if you recall back from our story, recall that IRS1 was the IRS givi

Ras is estimated to be responsible for 30% of human cancers. Most mutations in Ras prevent the protein from binding GTPase-activation proteins (GAPs). What is the effect of this mutation on the signal transduction?

• A. The GAP protein will activate too many Ras proteins.
• B. The Ras protein cannot be turned 'off' by GTP hydrolysis, so the signaling pathways remains activated.
• C. The Ras protein cannot be turned 'on' so the signaling pathway cannot be activated.
• D. The Ras protein is turned 'on' by the action of a protein kinase rather than GTP exchange.

Insulin is one of the hormones/growth factors that will activate the Ras and MAP kinase pathway. Concerning this system, all of the following are true EXCEPT

• A. Grb2 binds to the phosphorylated IRS-1.
• B. Grb2 binds to the phosphorylated IRS using its SH2 domain.
• C. Grb2 uses its SH3 domain to bind the GEF, Sos.
• D. Grb2 binds directly to the serine residues of the insulin receptor's alpha-subunits.
• E. The beta-subunits of the insulin receptor are phosphorylated on tyrosyl residues.

All of the following are true in the Ras and MAPK pathway EXCEPT:

• A. The occupied growth factor receptor autophosphorylates serine residues.
• B. Grb2 uses its Src homology 2 domain to bind to the phosphorylated IRS-1.
• C. Grb2 binds Sos in the Ras signal transduction pathway.
• D. In the MAPK pathway, Raf-1 phosphorylates MEK.
• E. In the MAPK pathway, ERK regulates transcription factors that regulate mRNA synthesis.

Guanine Exchange Factors (GEFs) bind Ras-GDP and promote dissociation of bound GDP to be replaced by GTP. GTPase Activating Proteins (GAPs) bind Ras-GTP and stimulates GTPase activity of Ras. How is the downstream signal affected by the presence of GEFs and GAPs?

• A. Signaling pathway increases in the presence of GAPs and decreases in the presence of GEFs.
• B. Signaling pathway increases in the presence of GEFs and decreases in the presence of GAPs.
• C. GAPs and GEFs both decrease the signaling pathway.
• D. GAPs and GEFs both increase the signaling pathway.
• E. GAPs and GEFs have no downstream effect on the Ras signaling pathway.

Here’s what students ask on this topic:

What is the role of insulin in the RAS pathway?

Insulin plays a crucial role in the RAS pathway by initiating a cascade of events that lead to cell growth. When insulin binds to its receptor, it activates the receptor's tyrosine kinase domains, which then phosphorylate IRS-1. The phosphorylated IRS-1 serves as a docking site for the adapter protein GRB2, which in turn recruits SOS. SOS acts as a guanine nucleotide exchange factor (GEF) that activates the monomeric G protein RAS by facilitating the exchange of GDP for GTP. The active GTP-bound RAS then triggers the MAPK signaling cascade, ultimately leading to the regulation of transcription factors involved in cell growth.

How does the MAPK pathway contribute to cell growth?

The MAPK pathway contributes to cell growth by transmitting signals from the cell surface to the nucleus, leading to the activation of transcription factors that promote cell division and proliferation. Once RAS is activated, it initiates a kinase cascade starting with RAF1 (MAPKKK), which phosphorylates and activates MEK (MAPKK). MEK then phosphorylates and activates ERK (MAPK). Active ERK translocates to the nucleus, where it phosphorylates various transcription factors such as ELK1, c-FOS, and c-JUN. These transcription factors then induce the expression of genes involved in cell cycle progression and growth, thereby promoting cell proliferation.

What mechanisms terminate insulin signaling as a growth factor?

Termination of insulin signaling as a growth factor involves several mechanisms. One key mechanism is the GTPase activity of RAS, which hydrolyzes GTP to GDP, converting RAS to its inactive form. This GTPase activity is inherently slow but can be accelerated by GTPase-activating proteins (GAPs). Additionally, phosphatases play a crucial role by dephosphorylating key proteins in the pathway, such as IRS-1, RAF1, MEK, and ERK, thereby reversing their activation. These combined actions help reset the signaling pathway to its inactive state, ensuring that the signal is transient and tightly regulated.

What are the key components of the insulin RTK signaling pathway?

The key components of the insulin RTK signaling pathway include the insulin receptor, IRS-1, GRB2, SOS, RAS, RAF1, MEK, and ERK. The pathway begins with insulin binding to its receptor, leading to the activation and phosphorylation of IRS-1. IRS-1 then recruits GRB2 and SOS, which activate RAS. Active RAS initiates the MAPK cascade by activating RAF1 (MAPKKK), which phosphorylates MEK (MAPKK). MEK then activates ERK (MAPK), which translocates to the nucleus to regulate transcription factors involved in cell growth. This pathway is crucial for mediating the growth-promoting effects of insulin.

How does insulin signaling differ between glucose metabolism and growth factor pathways?

Insulin signaling differs between glucose metabolism and growth factor pathways primarily in the downstream signaling components and the biological outcomes. In glucose metabolism, insulin signaling involves the activation of PI3K, PIP3, PDK1, and AKT, leading to the translocation of GLUT4 to the cell membrane and increased glucose uptake. In contrast, the growth factor pathway involves the activation of IRS-1, GRB2, SOS, RAS, RAF1, MEK, and ERK, leading to the regulation of transcription factors that promote cell growth and proliferation. While both pathways start with insulin binding to its receptor, they diverge to achieve different cellular functions.