Signaling Gone Wild

by Kevin Ahern, PhD

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    00:01 The last thing I want to talk about in this lecture relates to the process that I call signaling gone wild.

    00:06 And we’ve already seen a little bit of a hint of this already.

    00:09 Signaling proteins play important roles in growth and division as we’ve seen; the epidermal growth factor was a good example.

    00:17 I need to define a term here that I’m going to be using, so that you’re familiar with it.

    00:21 And it’s a term you’ve probably heard before, that term is oncogene.

    00:25 An oncogene is a mutated form of a gene whose activity can cause uncontrolled growth.

    00:32 I’ve described one already, that was the RAS protein.

    00:35 When we mutated the cellular RAS protein so that it could no longer cleave GTP, the RAS protein was left in the on state and the cell was left in a continual process of dividing.

    00:48 That mutated RAS was an oncogene.

    00:51 Well what was it before it mutated? It was a normal gene we call a proto-oncogene.

    00:57 So a proto-oncogene is a gene that has the ability to become an oncogene if it gets mutated.

    01:04 And you start to think, well mutation is one of the ways in which we can make cancer, in fact mutation is the primary way in which we can make cancer.

    01:12 How do we avoid mutation? Well there’s a variety of thoughts about that but one of which is to be careful of the food you eat, the water you drink and the air you breathe, because it’s materials inside of those things that can cause and favor mutation.

    01:27 Now mutations in signaling systems can often lead to tumor formation.

    01:31 They can happen in a variety of ways.

    01:33 One way are those mutations that affect the protein structure or function.

    01:39 Let’s imagine that we had a receptor protein, let’s say the EGF receptor protein that was left in the on state all the time.

    01:46 If the receptor protein was always communicating a signal to divide, that cell would become cancerous.

    01:53 We could also have mutations that affect the expression of a protein.

    01:57 Mutations that affect the expression of a protein may cause a protein that normally is present at a very low level in the cell doing very little to effect the signal to be made in much larger quantities and now really cause that signal to be heard like the kid in the classroom whose hand is going up all the time, “Teacher see me, see me, see me".

    02:16 That protein that has that effect is now causing the cell to divide, divide, divide.

    02:21 So the level of expression can affect whether or not a protein is an oncogene or not.

    02:27 And there are other mutations that can happen that may affect interactions with other proteins as well.

    02:32 Well let’s look at a couple of examples, I’ve already talked a little bit about RAS.

    02:36 So GDP bound RAS we learn, was inactive.

    02:39 And that the GTP activated it.

    02:41 The GTPase, because RAS is a very inefficient enzyme normally converts GTP to GDP over time.

    02:49 And so the signal gets turned off.

    02:51 Now I pointed out that mutations in RAS can cause RAS to cause that signal to always be on.

    02:58 And there’s two sets of mutations that can do that, that effect either amino acids 12 or 13, or amino acid 61; 12/13 depends on the type of RAS that we’re talking about.

    03:09 Each of these mutations prevents the RAS from being able to turn off that signal.

    03:16 Now what’s scary is, those are single based mutations; one mutation.

    03:20 You are one mutation away from potentially having a tumor.

    03:23 That’s kind of scary.

    03:25 Activated RAS stimulates cell division.

    03:29 So the more active RAS is, the more likely you are to have that cancer.

    03:32 I should also caution here that one mutation does not make a tumor.

    03:36 There’s actually a series of events that can make a tumor.

    03:41 Mutated RAS is the most common point mutation we find in cancer because it’s very simple to mutate RAS and have the effects that I’ve described here.

    03:50 Over 90% of pancreatic cancers for example, have a mutated RAS.

    03:54 And about 20% of all cancers that are known can have a mutated RAS.

    04:00 So RAS is very important in that process.

    04:03 Another example of signaling gone wild is that of the SRC protein.

    04:07 Now SRC protein is shown on the screen here.

    04:11 And it’s a tyrosine kinase but it’s not a receptor tyrosine kinase.

    04:15 It works internal to the cell.

    04:18 It participates in that signaling process that I described before.

    04:22 So we saw a bunch of proteins that got phosphorylated in the EGF signaling pathway.

    04:27 So there are many kinases in the cell that participate in the signaling process.

    04:32 SRC proteins are-- participate in a variety of signaling processes.

    04:36 And they have the effect not of activating cell division but actually of inactivating cell division.

    04:44 So phosphorylation of SRC’s tyrosines doesn’t cause it to be turned on, it causes SRC to be turned off.

    04:52 That means that normally when the signaling process comes along and it hits SRC, it’s telling the cell, “Don’t divide". And SRC will stop that cell from dividing. Well what happens if SRC itself is mutated so that those phosphates can’t be put onto it. What happens is dephosphorylated SRC will act to stimulate cell division. So, you get it if you've got a phosphate on there, you get it if you don’t have a phosphate on there. You begin to get the idea that it’s important to have the proper phosphate on at the proper place, at the proper time, or a cell is likely to become cancerous. Mutations that affect any phosphorylation part of SRC or enzymes that affect that SRC phosphorylation will affect SRC’s ability to properly communicate that signal and result in a cancer. Now, there are proteins that activate SRC by dephosphorylating it that have also been detected at elevated levels in various cancer cells. So not only is the process of putting on the phosphate important, but the removal of that phosphate may also affect SRC’s ability to properly communicate that signal.

    06:01 Well I’ve said a fair amount then about the phosphorylation or dephosphorylation of SRC and it’s ability to affect the cell’s division.

    06:08 So how does this overall process actually work? Well the phosphorylation of tyrosines that are described in SRC actually prevent the access of other proteins to SRC’s SH2 domain.

    06:21 That will prevent SRC from interacting with those proteins because SH2 domains interact with phosphorylated tyrosines.

    06:29 If the SH2 domain is covered up as it is when the SRC is phosphorylated, then SRC will not participate in the signaling process that stimulates cell division.

    06:40 Consequently, SRC is therefore out of the picture.

    06:43 Mutations that change the tyrosines leave the protein always activated because there’s always access to those-- the SH2 domains.

    About the Lecture

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

    • Signaling Gone Wild
    • Mutations Affecting Protein Structure/Function

    Included Quiz Questions

    1. They are genes whose structure or function has been disrupted.
    2. They are unmutated genes known as proto-oncogenes.
    3. They play normal roles in cell growth and division.
    4. They are not influenced by environmental factors.
    1. It is a tyrosine protein kinase that is not a receptor.
    2. It is activated by phosphorylation.
    3. It prevents cells from dividing when it has no phosphate.
    4. It is a tyrosine kinase receptor.
    1. 12/13 or 61 amino acid position.
    2. 21/31 or 16 amino acid position.
    3. 21 or 31 amino acid position.
    4. 21 or 16 amino acid position.
    5. 31 or 16 amino acid position.

    Author of lecture Signaling Gone Wild

     Kevin Ahern, PhD

    Kevin Ahern, PhD

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