Receptor Tyrosine Kinase Pathways – Second Messenger Systems

by Georgina Cornwall, PhD

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    00:00 Let's step back for a moment and reconsider what a protein kinase is. A protein kinase is an enzyme that phosphorylates other proteins. Sometimes as we've previously seen, these protein kinases are intracellular protein kinases. Other times, the protein kinase is actually embedded in the cell membrane. Receptor tyrosine kinases are a perfect example of these embedded protein kinases.

    00:35 So here we have a protein that is about to be phosphorylated by a protein kinase.

    00:42 Recall the protein kinase is going to take its phosphates off of either ATP or we've seen GTP in our examples of G-proteins. And it's going to form ADP but stick the phosphate right on to this protein. So protein kinase an enzyme that phosphorylates any other protein.

    01:05 We can also have dephosphorylation which will inactivate. In the last lecture we looked at how we could turn things on with phosphorylation or we could actually turn things off with phosphorylation.

    01:18 The example might be if we phosphorylate a protein with protein kinase and it activates that cascade, or we could phosphorylate a protein with a protein kinase. And that phosphorylated protein could perhaps go and grab one of the intermediates and stop it working in the cascade. Much like taking out a firemen and not letting him do his job. So, the other thing that can happen is we can have this protein that's been phosphorylated, recycled. Its been dephosphorylated because usually the phosphorylated protein is going to transfer its phosphate to another protein. And then that one to another protein. And so on and so forth down the cascade until we actually have our full blown cellular response. Recall that I mentioned receptor tyrosine kinases are involved in general cell functions. The everyday life of a cell. Things like cell cycle and cell growth. Cell migration from place to place. Cell metabolism, cell proliferation and many growth factor regulation processes.

    02:26 So growth factors often work through receptor tyrosine kinases to form their effects in growth and development. Before we get into the details of how these receptors work and what happens in the cascade, let's look at the anatomy of a receptor tyrosine kinase.

    02:44 What you see here are two receptor tyrosine kinases. They each have a single transmembrane domain, the alphahelical portion. They also have a receptor ligand binding domain on the outside of the cell.

    03:01 And on the inside of the cell we have the actual receptor tyrosine kinase protein. So here, the protein kinase is attached to the receptor that's on the outside of the cell. Rather than having an intracellular protein kinase which is what we've looked at previously. So once a ligand binds to the receptor portion of the receptor tyrosine kinase, we'll see dimerization.

    03:28 That is these two subunits come together. So as they come together, they phosphorylate each other.

    03:35 Recall that the portion dangling inside the cell is the actual protein kinase portion. And because it's a protein kinase it can take phosphates off of ATPs and stick them on the other receptor tyrosine kinase.

    03:49 So in this fashion they diamerize, they join together. The phosphotyrosine regions, the tyrosines with the phosphates on the side actually act as docking sites for other proteins involved in the signal transduction cascade. The response that we get from a receptor tyrosine kinase diamerization is completely dependent on the type of response proteins that are involved. Most often these are enzymes.

    04:20 In order for proteins to dock or these enzymes to dock on to the phosphotyrosines, we often need docking proteins. So docking proteins will help other enzymes dock on to the phosphotyrosine sites.

    04:36 In addition to docking proteins, sometimes we need adapters. Sort of like when you're plugging in electricity in a foreign country. You need an adapter to make sure it fits directly on to this particular prongs or phosphates that are sticking out of the phosphotyrosines. So once these two are diamerized and we've started to activate that protein cascade, there are a multiple different options of things that will happen. Shortly we'll take a look at a couple of great examples of a cascade that could result from receptor tyrosine kinase activation. So in the case of insulin, it binds to the extracellular receptor domain. And then it activates the receptor tyrosine kinases. They autophosphorylate each other. And then we have the insulin response protein that's going to bind; It's a docking protein, it's going to bind to those phosphate prongs on the receptor tyrosine kinase. Following that it's going to pass the phosphates on to other proteins that then result in activating glycogen synthase.

    05:51 So we're going to phosphorylate a bunch of proteins. Essentially that result in transcription and translation of things that make glycogen synthase. And then glycogen synthase is going to take glucose molecules and stick them togeher to form glycogen. So in this sense, insulin is reducing the sugar that's floating around and free and ready for metabolism and stuffing it into glycogen molecules and thus reducing blood sugar and increasing the storage of carbohydrates. So how is amplification of these signals actually accomplished. There is a great example by looking at mitogen activated protein kinase cascades or MAP cascades. In which kinases are activated by a series of protein kinases.

    06:42 So this mitogen kinases are stepwise activated. And in the diagram we saw earlier you can see that each step along the way there is potential for amplification of the signal.

    06:54 First of all we have a module of protein kinases. And we'll see how these are associated shortly.

    07:02 And they will phosphorylate each other. So here we have an example of the phosphorylation being passed down through each of these activating kinases. It's not important for us to know precisely what those are but just get the general scheme of how each step of the way we're passing the phosphate on and we could be amplifying the signal cause there's more protein kinases and thus more phosphorylation.

    07:27 So finally we get the phosphorylation of MAP kinase. And as we're going to see shortly MAP kinase plays a particular role in linking things together to the cellular response. So again as we move through each step of that mitogen activated kinase cascade, we can see that this signal can be amplified further and further and further until we eventually get a cellular response. I mentioned that these were grouped in a module. This is because we have things called scaffold proteins. They're essentially a protein that holds each of the protein kinases involved in this mitogen activating kinase cascade in one protein subunit. Otherwise, you'd have these things freely floating around the cell and it would be really hard to get them together. So scaffold proteins hold groups of related proteins in a pathway together so that we can keep the response fairly localized. The cellular response could result in many possible targets. We could be increasing the rate of transcription and translation.

    08:38 Phosphorylating transcription factors so that they can dock on to the DNA and help activate that process.

    08:45 We'll look at what some of those specific proteins are in a future lecture. But activating gene expression is one of the keys of these receptor tyrosine kinase pathways. Molecular switches also link receptor tyrosine kinases to MAP kinase cascades. Let's take a look at an example of a molecular switch.

    09:10 These switches can link external signals to internal transduction pathways and they are sometimes broken and that can result in cancer. Again when we look at cell division and cell cycle controls, we'll be able to see one of those mechanisms in play. So receptor tyrosine kinases are often linked to protein kinase cascades by molecular switches. Here is an example of a molecular switch.

    09:44 Often the molecular switches are activated by external cell signals at another receptor location.

    09:51 We'll see how they come together shortly. So we have this external signal in this case activating guanine exchange factors. Guanine exchange factors will take GTP, guanine triphosphate and take the phosphates off transferring them to another protein. In this case, we're looking at RAS. RAS is activated by the transfer of GTP onto itself. And it is inactivated when we remove the GTP.

    10:28 The RAS class of proteins is a pretty active area of research at this moment, but here we can see precisely how it works as a molecular switch. So again another receptor activates guanine exchange factors which help phosphorylate the protein RAS or dephosphorylate the protein RAS. So when we remove the ATP, RAS is deactivated. And when we add the GTP, RAS is activated. So here is a summary of how a receptor tyrosine kinase pathway might work including the receptor tyrosine kinase itself, the MAP cascade, and our RAS protein molecular switch. So we have, RAS as a switch in the middle and that links the receptor tyrosine kinase to the MAP kinase cascade that we've previously examined. And that will then impact what sorts of cellular responses we get by activating a variety of different transcription factors.

    11:42 Again the response we get depends entirely upon which proteins are activated, which gets quite complex because that depends on all sorts of other receptors coming in to the cell. So again, how do the cells really decide what it is they want to do. Well they have to choose based on what the DNA says which people in the room they're listening to. If you recall the analogy of having a room full of people.

    12:10 It's very loud and bustling. How do you communicate with the people right next to you.

    12:15 The cell gets to choose which signals that it listens to. By depending on which receptors are in its cell membrane. So as you can see there are multiple levels for modulation of these signal transduction systems. The more players there are, the more complex it is. In fact to me, it's often surprising that any of it works out at all.

    About the Lecture

    The lecture Receptor Tyrosine Kinase Pathways – Second Messenger Systems by Georgina Cornwall, PhD is from the course Cellular Structure.

    Included Quiz Questions

    1. Most second messenger systems fall into either RTK pathways, or G-protein coupled receptor pathways
    2. RTK pathways are generally involved in regulation of normal cell processes
    3. G protein coupled pathways are generally involved in mediating structural and metabolic changes.
    4. Rarely involve a multi step signal amplification
    1. dimerization of two protein kinase receptor subunits
    2. autophosphorylation
    3. docking proteins and adapter proteins
    4. G-protein kinases
    1. Insulin binding to the insulin-related RTKs system leads to immediate separation of two RTKs subunits to stop the down streaming of the signal cascade.
    2. RTKs are membrane-embedded kinase proteins which play an important role in general cell functions like cell cycle, growth, migration, and metabolism.
    3. The maintenance of blood sugar via insulin involves insulin linked RTKs system.
    4. Binding of ligand to the extracellular receptor domains causes the autophosphorylation of intracellular domains at serine, threonine, and tyrosine residues.
    5. Anatomical RTKs are composed of two RTKs monomer units, each with the single hydrophobic α-helical transmembrane domain, which dimerizes upon the binding of the ligand on the receptor sites.
    1. Protein kinase ---- phosphorylation of proteins
    2. Docking proteins ---- Helps other proteins to get docked on the phosphotyrosine sites of RTKs
    3. Phosphotyrosine sites ---- Docking sites on RTKs for the phosphorylation of proteins
    4. Protein phosphatase ---- Dephosphorylation of proteins
    5. Adaptor proteins ---- Facilitate downstream signaling events
    1. …involves in the organization of signaling cascade proteins/components into a highly ordered macromolecular complex for efficient signal transduction.
    2. …are active enzymatic components of the signal cascade.
    3. …involves in the transfer of phosphate groups from the kinases or phosphatases to the substrate proteins to switch on or off them.
    4. …directly deals with the reception of an external signal to stimulate the cellular responses.
    5. …act as molecular switches.
    1. The transmembrane domains of the receptor molecules act as molecular switches to phosphorylate the intracellular domains to start downstream signal transduction of external stimulus.
    2. Ras, a binary signaling molecular switch (a G-protein), act as connecting links between receptor tyrosine kinases and mitogen-activated protein kinases.
    3. Ras proteins are activated and deactivated by Guanine nucleotide exchange factors (GEFs) and GTPase activating proteins (GAPs), respectively.
    4. Ras system usually regulates the cell cycle and division by regulating the cell cycle genes through the activation of the mitogen-activated protein (MAP) kinase cascade.
    5. The breakdown of intramolecular switches leads to cancers due to deregulated cell cycle and cell division events.

    Author of lecture Receptor Tyrosine Kinase Pathways – Second Messenger Systems

     Georgina Cornwall, PhD

    Georgina Cornwall, PhD

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