Signaling Pathways

by Richard Mitchell, MD, PhD

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    00:00 There are other pathways and that's what we're gonna talk about next.

    00:03 Signaling pathways. Typically, of a ligand that's been secreted by some other cell, either nearby or far away.

    00:10 That ligand will wander around in the extracellular fluid, until it encounters its receptor, and usually, there's a very high affinity.

    00:19 So, this ligand just doesn't go anywhere, it will only go specifically to its intended receptor.

    00:25 That receptor exists usually as a combination of proteins in the membrane, but they're not connected yet.

    00:32 They're just kinda sitting there and they're floating around in their lipid bilayer.

    00:36 All right, now ligand binds. Those two halves of the receptor come together.

    00:42 And when those two halves of the receptor come together, or it may be three or it may be four, but they come together, they form now a signaling little factory that's able to send cellular responses inside the cell.

    00:56 And we'll talk about various ways, but this is the big concept.

    01:00 We bind a ligand, we get a conformational change of a receptor, and then magic happens.

    01:06 Let's talk about some of the magic. So, this is gonna get a little bit more specific.

    01:09 Do not get too bugged down.

    01:11 In fact, don't get bogged down at all in the little details and the specific labels.

    01:15 But do hang onto the bigger picture of how this works.

    01:20 So, we have a growth factor.

    01:21 Not specified, but a growth factor, and it's going to bind typically, classically, to a receptor tyrosine kinase.

    01:28 It's called a tyrosine kinase because there is intrinsic enzymatic activity that will phosphorylate tyrosines. Hence the name RTK.

    01:37 Okay, so right now, that receptor is totally inactive, because no growth factor has bound to it.

    01:43 And we see that its already got certain phosphate groups on it.

    01:47 It's got some other associated groupies hanging onto the cytoplasmic phase.

    01:52 Okay, growth factor binds, we get rearrangement.

    01:55 We get proteins that are changing conformations, and now, we're gonna get secondary phosphorylation of other downstream proteins because of that conformational change.

    02:06 The receptor tyrosine kinase now becomes active and will phosphorylate.

    02:10 And it phosphorylates, for example, the Ras-GDP complex.

    02:15 That will in turn act on phosphatidylinositol-trisphosphate.

    02:21 Remember that we talked about phosphatidylinositol, mean one of those protein -- one of those lipids on a cytoplasmic phase that was important for signaling? Here's where it becomes important to talk about it.

    02:34 So, the growth factor has caused phosphorylation, which has caused other molecules to be activated, which is now activating PIP3 kinase to phosphatidylinositol to phosphate, and diacylglycerol, and those will then activate a cascade of additional molecules, and magic happens inside the cell.

    02:55 We have signaled from the outside of the cell to the inside of the cell.

    02:59 This kind of cascade is also important to keep in mind, because each one of these steps is potentially prone to mutations, and that will cause potentially cancer, or is subject to inhibition.

    03:12 So, the receptor tyrosine kinases.

    03:14 There are lots of inhibitors that pharmacology companies have made that will inhibit these somewhat selectively.

    03:21 And all these other kinases on the other side of the equation will also be potentially inactivate-able.

    03:27 So, they're targets. So, although it may seem like, "Oh, my god, this is so much detail.

    03:32 I don't need to know all of this detail," yes, you do, because these are potential targets for therapies.

    03:37 Okay, so we're gonna look at other variations on this theme of signaling.

    03:43 Other ways that we can get a signal across the membrane into the nucleus.

    03:48 And we've already seen the one with the receptor tyrosine kinase.

    03:52 Here's another one. We have a ligand coming into a receptor.

    03:55 That is then causing a dimerization of the receptor with a conformational change, and we're getting autophosphorylation of that JAK complex.

    04:07 So, the little yellow balls of phosphate are now changing the way that that JAK component looks.

    04:14 We now have new enzymatic activity related to that phosphorylated JAK.

    04:21 And an intracellular protein called STAT gets phosphorylated too.

    04:25 So, it's a sequence. It's a cascade of events, and remember, long ago, we talked about cascades.

    04:30 Now, we have phosphorylated STAT.

    04:33 Well, phosphorylated STAT can now excess the nucleus.

    04:37 Before it got phosphorylated, it couldn't do it.

    04:39 It would not be able to be transported across the nuclear membrane or the nuclear pores into the cell, into the nucleus.

    04:45 And now, here we have phosphorylated STAT.

    04:48 After JAK phosphorylation, that will allow this thing to get to the nucleus where it can sit on promoter sequences and start transcription of various genetic sequences.

    05:01 So, the phosphorylated factor sits, just like it says there, and will induce transcription. Okay.

    05:09 Another one. So, these were all hydrophilic ligands.

    05:13 These are ligands that will not pass across the membrane, because they're large and they're charged.

    05:19 They're actually a subset of ligands that we use for signaling around the body that do get across membranes really easily.

    05:26 These are hydrophobic ligands.

    05:28 They are usually cholesterol-based, and an example is estrogen.

    05:32 Testosterone is another example. Interestingly, vitamin D is another example.

    05:37 These move across membranes with impunity because they are largely hydrophobic and because they have a big cholesterol core.

    05:45 So, estrogen, for example, now, doesn't need a receptor on the outside.

    05:49 It permeates directly across the membrane and every cell in the body, and where there are specific cytoplasmic intracellular estrogen receptors.

    05:59 It now will bind, and by virtue, the binding of the estrogen to its receptor, we get translocation into the nucleus in gene transcription.

    06:09 So, just another halfway, but this time, of a hydrophobic ligand.

    About the Lecture

    The lecture Signaling Pathways by Richard Mitchell, MD, PhD is from the course Cellular Housekeeping Functions.

    Included Quiz Questions

    1. Vitamin D receptor
    2. Vitamin B12 receptor
    3. Insulin-like growth factor receptor
    4. Growth hormone receptor
    5. Insulin receptor
    1. It has intrinsic enzymatic activity.
    2. It usually binds to cholesterol-based hormones.
    3. Once it binds to its ligand, it is translocated into the nucleus.
    4. It is an example of a glycosylphosphatidylinositol-linked protein.
    5. Targeted anticancer drugs work by activating this receptor.
    1. Autophosphorylation
    2. Dephosphorylation
    3. Translocation of the ligand-receptor complex
    4. Activation of the RAS protein
    5. Activation of MAP kinase

    Author of lecture Signaling Pathways

     Richard Mitchell, MD, PhD

    Richard Mitchell, MD, PhD

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