Receptor Tyrosine Kinase Signaling

by Kevin Ahern, PhD

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    00:01 Next I’d like to talk about another very interesting set of receptor proteins.

    00:06 These are known as the receptor tyrosine kinase proteins and they’re involved in very important signaling that help to control the cell’s decision to divide or not to divide.

    00:17 Now, receptor tyrosine kinases or RTKs are also membrane bound proteins.

    00:24 And these are also kinases.

    00:26 That means that they put phosphates onto other proteins.

    00:30 But unlike protein kinase A which puts phosphates onto serines and threonines, RTKs put phosphates onto the side chains of tyrosines of target proteins.

    00:40 And it turns out that phosphorylation of tyrosines gives a very different kind of a signal than phosphorylation of serines and threonines.

    00:47 We can see the phosphorylation of tyrosine happening as a result of catalysis by RTK in this process right here, and they’re simply the addition of a phosphate to the hydroxyl group of tyrosine.

    00:58 RTKs play very important roles as I said in regulating whether or not cells are going to divide.

    01:05 Now RTKs usually work as a result of dimerization.

    01:10 What does that mean? Well RTKs are found in cell membranes as individual units; an RTK here and an RTK over here.

    01:18 Each of those individual units as they exist will be inactive, but the binding of a hormone causes the two subunits, or the two units of the protein to actually come together into one, that’s a dimer.

    01:30 That dimer is then active.

    01:32 So the activation of an RTK happens by the binding of the hormone that causes dimerization of individual subunits.

    01:43 We see schematically here, two RTKs, individual subunits embedded in a lipid bilayer.

    01:49 There’s the lipid bilayer.

    01:50 And we see the outside of the cell is at the top and the inside of the cell is to the bottom.

    01:54 The RTK monomers have a binding site for the hormone.

    01:58 They also have what’s known as a transmembrane α-helix, and that’s just simply a part of the protein that projects through that lipid bilayer.

    02:06 Like the seven TM I described before, they have a part that is outside, that grabs the message, and a part inside that communicates the message.

    02:16 It’s the cytoplasmic domain of the tyrosine protein kinase that becomes activated on dimerization.

    02:22 And when it’s in the monomeric form, it’s inactive as you see here.

    02:27 Well here’s the activation process.

    02:29 We see the binding of a hormone occurring here.

    02:32 And the binding of the hormone actually causes the two units to come together.

    02:37 The bottom portion of these protein subunits as I’ve shown here are actually tyrosine kinases.

    02:43 And now they’ve been activated by being brought into close proximity of each other.

    02:48 These tails of these individual RTKs phosphorylate each other.

    02:54 One phosphorylating the other, which in turn causes each of them to become much more active than they were before.

    03:01 Those RTKs are active and they can do one of two things.

    03:05 They can either put phosphates on other proteins that are inside the cell or the fact that they have phosphates on them becomes a target for binding of other proteins to them.

    03:15 We’ll see that happen here.

    03:18 In any event, what we’ve created as a result of binding of the hormone is with activated of the tyrosine kinase of these RTKs.

    03:27 So, one of the things that can happen as I said is the binding of other proteins to these phosphates that are on there. The binding of other proteins is mediated through a special binding part of proteins called an SH2 domain. SH2 domains recognize phosphotyrosines and grab a hold of them. And we can see that actually happening here in formation of what’s called a signaling complex. The signaling complex has multiple protein subunits which I’ve drawn with some oval and triangles and a star.

    04:00 And this signaling complex will help communicate that message into the cell.

    04:08 Now, looking at what’s been happening here, we see the binding of the hormone to the RTK in the membrane.

    04:13 The receptor dimerizes, there’s an autophosphorylation that happens.

    04:17 And by the way, these happen in all of the RTKs that I’ll describe.

    04:21 As their signaling complex that becomes assembled.

    04:23 And now the message is communicated into the cell.

    04:27 So here’s one RTK known as the insulin receptor.

    04:31 The insulin receptor as its name suggests is a protein in the membrane that binds to insulin.

    04:38 And on the inside it has the tyrosine kinase.

    04:41 And that tyrosine kinase allows it to phosphorylate things.

    04:45 Now insulin receptor is actually a little unusual in that it doesn’t start as a monomer.

    04:50 It’s one of the few RTKs that actually start as a dimer.

    04:53 The two units are already held in close proximity.

    04:55 But they don’t become active until they bind to the insulin.

    04:59 It’s the binding of the insulin that causes them to become activated.

    05:02 But the activation doesn’t require them to come together, they’re already together.

    05:07 So here’s this process that happens with the insulin RTK - autophosphorylation.

    05:13 And now we see the beginning of the signaling complex.

    05:16 The signaling complex starts with the binding of a protein called IRS-1.

    05:20 And IRS-1 has multiple things that it can do.

    05:24 It can interact with other signaling pathways as you see in the arrow going upwards, or in the case of the insulin pathway, that is the response of insulin.

    05:32 What it does, is it activates another kinase known as PI3.

    05:38 PI3 catalyzes the formation of a molecule called PIP3.

    05:43 PIP3 is a second messenger.

    05:45 It’s a small molecule, meaning it’s not a protein and it’s helping to communicate that message.

    05:50 PIP3 interacts with a protein called PDK1, which is another kinase and activates it.

    05:58 Well finally, activation of Akt kinase causes another protein to move to the cell surface.

    06:04 This other protein is known as GLUT4.

    06:08 What is GLUT4? GLUT4 stands for glucose transport protein 4.

    06:15 What does GLUT4 do? Well when it moves to the cell membrane, it embeds itself in the membrane.

    06:20 And the function of GLUT4 is to pull glucose out of the extracellular part of the cell into the cell, and have the glucose available for the cell.

    06:30 That’s important because that’s ultimately what insulin is trying to do.

    06:34 Our body makes insulin after we have a meal, and our blood glucose levels rise.

    06:40 Blood glucose is actually hazardous for the body.

    06:44 To reduce the blood glucose level, insulin binds to a receptor and stimulates the cells to take up that glucose, thereby reducing the level of glucose in our bloodstream.

    06:54 So this overall process which had many steps, had one aim.

    06:58 And that one aim was to get the cells to take up glucose.

    07:03 Well in addition to causing glucose to come into the cell, one of the things that the cell has to do is to deal with that glucose.

    07:10 Well glucose is actually what I describe as a poison for a cell.

    07:14 That means too much of it really causes a problem.

    07:17 So the cell doesn’t want to have too much free glucose sitting around inside of itself.

    07:23 How does it deal with that extra glucose? Well if you remember back to the pathway that I showed you for the glycogen breakdown and glycogen synthesis, I showed that phosphoprotein phosphatase was involved in that last step that inactivated the breakdown of glycogen and activated the synthesis of glycogen.

    07:42 That phosphoprotein phosphatase is turning off glycogen breakdown and turning on glycogen synthesis.

    07:50 What does it take for glycogen synthesis? Glucose.

    07:53 So that glucose that’s coming into the cell is built into glycogen, and glycogen is not a poison for the cell.

    07:59 A pretty cool process.

    08:03 Now, insulin signaling happens in a reciprocal fashion to epinephrine signaling.

    08:08 And I want to show you that in this slide.

    08:10 The β-adrenergic receptor pathway, which was the pathway that activated the breakdown of glycogen, operates in the manner that you see here.

    08:18 And I won’t go through all the individual steps.

    08:20 The net upshot of that is that glycogen is broken down and blood glucose levels rise.

    08:26 This is good if somebody’s chasing you because you want the energy to be able to run away.

    08:30 After you’ve had a meal however, you’ll want to deal with that glucose.

    08:33 That involves the insulin receptor pathway which does a couple of things.

    08:38 One, is it’s moving that GLUT to the membrane so that the membrane-- that the glucose can now move across the membrane and into the cell.

    08:45 And phosphoprotein phosphatase is activated so that the glycogen breakdown can stop and the glycogen synthesis can start. As a result of insulin action, glycogen is made and blood glucose levels fall. These processes are happening in exactly the opposite fashion in the reciprocal regulation that I’ve describe before.

    About the Lecture

    The lecture Receptor Tyrosine Kinase Signaling by Kevin Ahern, PhD is from the course Hormones and Signal Transduction. It contains the following chapters:

    • Receptor Tyrosine Kinase Signaling
    • Means of Activation
    • Insulin Receptor

    Included Quiz Questions

    1. They autophosphorylate on binding their hormone.
    2. They are active primarily as monomers.
    3. They remove phosphate from proteins.
    4. They do not regulate cell proliferation.
    1. It requires dimerization.
    2. It can occur on the outside or inside of the cell.
    3. It turns off the signaling system.
    4. SH2 domains have no role to play.
    1. It has proteins that bind to phosphotyrosines.
    2. It involves the activation of intranuclear receptors.
    3. It transmits signals from the inside of the cell to the outside of the cell.
    4. It has proteins with SH2 domains.
    5. It communicates the message to the rest of the cell.
    1. It activates phosphoprotein phosphatase.
    2. It activates the cyclic AMP pathway.
    3. It causes blood glucose levels to rise.
    4. Insulin signaling occurs in the same manner as epinephrine signaling.

    Author of lecture Receptor Tyrosine Kinase Signaling

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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    Excellent teacher!
    By Charles P. on 14. May 2019 for Receptor Tyrosine Kinase Signaling

    I have taken biochem as an undergrad, grad. and post grad and I've never had anyone explain things as clearly. Dr. Ahern is one of the best teachers I've ever encountered. Thank you!