Epidermal Growth Factor Receptor (EGFR)

by Kevin Ahern, PhD

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    00:01 The next receptor system I’d like to talk about is that of the epidermal growth factor receptor or the EGFR.

    00:07 Like the other receptors I’ve been talking about, the epidermal growth factor receptor is a receptor tyrosine kinase.

    00:14 It dimerizes on binding to epidermal growth factor or EGF.

    00:19 Now EGF is a protein that’s involved in the growth and proliferation of cells.

    00:25 And EGF helps to control that overall process.

    00:31 So let’s take a look at the signaling pathway up close.

    00:34 We see on this figure, the binding of EGF shown in green, on the outside part of the cell to the EGF receptor.

    00:42 The receptor here has dimerized and is holding that EGF in the cell membrane.

    00:47 We can see some accessory proteins that have come along and have started to form the signaling complex on the inside of the cell.

    00:55 This includes a protein known as GRB2.

    00:57 And GRB2 is binding to phosphoytyrosines that are on the cytoplasmic side of the cell, on the EGF receptor.

    01:07 That autophosphorylation that I described before has happened here.

    01:11 And this GRB2 has an SH2 domain that recognizes those phosphoproteins and binds to them.

    01:17 GRB2 binds to another protein known as SOS, which for our purposes here is insignificant.

    01:23 But what is significant is the next protein that binds which is known as RAS.

    01:27 Now RAS is a protein that’s very intimately involved in controlling the cell’s decision to divide.

    01:34 RAS is a protein that is very much like the G-protein that I described before in the beta-adrenergic receptor.

    01:40 It’s of similar size and it also binds to guanine nucleotides.

    01:46 The guanine nucleotide that it binds to here is GDP.

    01:50 And when it gets activated, which is what’s happening in this process, the GDP is replaced by GTP and RAS is now active to go do its thing.

    02:00 And active RAS prepares a cell for division.

    02:05 Well there’s still more to this pathway; RAS in turn goes to another protein known as RAF which is a kinase and activates it.

    02:14 RAF puts a phosphate onto another protein known as MEK, which is a kinase which puts a phosphate onto another protein known as MAPK, which is of course a kinase that puts phosphates onto other proteins as we can see here.

    02:27 Now, the order of this for our purposes isn’t significant.

    02:30 What’s important though is what’s happening in the overall process.

    02:34 This cascade of phosphorylations that’s happening is causing a bunch of different proteins to become active, and it’s affecting at the very bottom, some proteins that are known as transcription factors.

    02:47 These transcription factors become activated by the addition of the phosphate.

    02:51 And they move into the cell nucleus as you can see here to co-activate gene expression.

    02:58 The genes that they’re activating will stimulate the cell to divide.

    03:02 So epidermal growth factor has favored the process of cell division.

    03:06 Well before I go further I need to say an interesting word about RAS.

    03:10 RAS is actually a family of related proteins, it’s not just one, there are actually several.

    03:16 Each of these proteins is monomeric, that differs from what we saw with the G-proteins before; they had the heterotrimers that we had associated with the β-adrenergic receptor.

    03:26 RAS proteins can bind guanine nucleotides as we saw.

    03:30 And this human RAS that’s shown here is bound to a GDP.

    03:35 RAS swaps GDP for GTP when it gets activated by that signaling complex that I showed earlier.

    03:43 Now like the α subunit of the β-adrenergic receptor, RAS is also a bad enzyme.

    03:50 It very slowly cleaves GTP to GDP, meaning that RAS turns itself off over time.

    03:59 Well that’s good, because you don’t want a cell continually turned on and continually dividing because that becomes known as a cancer.

    04:07 What we said before was important for a cell to be able to turn off a signal just like it was important to turn on a signal.

    04:13 And that’s particularly important for RAS as we have seen.

    04:16 Now RAS as I said, is a bad GTPase.

    04:19 It converts GTP into GDP and turns itself off.

    04:24 What happens if RAS can’t turn itself off? That happens sometimes.

    04:28 And it happens too frequently unfortunately.

    04:30 They are what are called point mutations or single base changes within the RAS coding sequences that if they change, they can affect the ability of RAS to cleave GTP.

    04:42 If they inhibit RAS’s ability to cleave GTP, RAS is always left in the on state.

    04:48 Well, you saw from the last slide what happens if it’s left in the on state continuously, the cell will continue to divide uncontrollably and that can lead to cancer.

    04:56 And RAS is implicated in numerous human cancers.

    05:00 Now other things need to be turned off as well.

    05:02 The RTK that was the EGF receptor that I talked about specifically here also has to be turned off.

    05:08 How does it get turned off? Well, like the β-adrenergic receptor, it gets internalized into the cell in a process known as endocytosis, thus removing it from being part of the signaling processes.

    05:20 The phosphatases that get stimulated in the schemes that I’ve shown before are proteins that remove phosphates from other proteins.

    05:27 And this whole cascade that I showed before, there was a whole series of phosphorylated proteins.

    05:33 A phosphoprotein phosphatase acting on them inactivates the entire pathway with a single action.

    05:40 That’s pretty cool.

    05:42 Now you might wonder, how is it that phosphoprotein phosphatase itself gets inactivated? And it turns out that it gets inactivated by an interesting phosphorylation process.

    05:52 I wanted to take a minute and show you that.

    05:54 On the right part of the screen you can see the phosphoprotein phosphatase that’s in green, that is bound to a protein called Gm; that’s not a G-protein.

    06:03 It’s just a muscle protein called Gm.

    06:05 In the form that you see on the top, it’s active.

    06:08 But a phosphorylation of the Gm, causes the Gm to release the phosphoprotein phosphatase.

    06:16 That leaves the phosphoprotein phosphatase less active.

    06:20 You also see floating out there, an inhibitor.

    06:23 The inhibitor by itself doesn’t bind to the phosphoprotein phosphatase and inhibit it.

    06:28 Rather what it does, is it waits for the inhibitor to get itself phosphorylated.

    06:34 When the inhibitor gets phosphorylated, phosphoprotein phosphatase binds to it and is then completely inactivated.

    06:41 So that’s how it gets inactivated.

    06:43 The question then is, when does it get inactivated? And it gets inactivated by action of protein kinase A.

    06:52 Now think about this reciprocal regulation.

    06:55 This reciprocal regulation is causing one set of enzymes to become active on binding of one hormone, and another to become inactive, and then flip them with the other hormone.

    07:04 So in the case of epinephrine for example that I talked about, it was stimulating proteins that were important in breaking down glycogen.

    07:12 And insulin was important for stimulating proteins that were making glycogen.

    07:16 We see that that reciprocal regulation extends all the way down to turning off proteins like phosphoprotein phosphatase.

    07:23 Pretty cool process.

    About the Lecture

    The lecture Epidermal Growth Factor Receptor (EGFR) by Kevin Ahern, PhD is from the course Hormones and Signal Transduction. It contains the following chapters:

    • Epidermal Growth Factor Receptor (EGFR)
    • RAS

    Included Quiz Questions

    1. It is involved in the growth and proliferation of cells.
    2. It is located in the nucleus.
    3. It dimerizes upon binding EGF.
    4. It is a type of receptor tyrosine kinase.
    5. It can stimulate growth in the absence of hormones.
    1. It is focused on stimulating transcription.
    2. It requires that RAS be a dimer to function.
    3. It gets a phosphate put onto its GDP to make GTP.
    4. It inactivates RAF.
    1. They can inactivate kinase enzymes.
    2. They activate kinase enzymes by phosphorylating them.
    3. They are involved in regulating the cascade induced by RAS.
    4. They can be inactivated by a phosphorylated inhibitor.

    Author of lecture Epidermal Growth Factor Receptor (EGFR)

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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