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Lecture 24.docx

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Biological Sciences
Dan Riggs

First we will talk about a very conserved pathway called the MAP kinase cascade. Then we will talk about pathway interactions and later we will talk about apoptosis. Last time we talked about receptor tyrosine kinase this type of communication isn't the only thing this category of receptors does. Many of them are involved in governing cell cycle control, that is, governing cell division. When the appropriate signal comes in, it might be in the form of a growth factor type of hormone and it gets together with its receptor and this activates a couple of intermediates called RAS and RAF. Ultimately this activates the MAP kinase cascade. The MAP kinase cascade for the most part deals with the commitment of cells to cell proliferation. Figure 15 – 20 shows what to gets the pathway rolling towards cell division. The growth factor comes in and binds to a receptor if it exists. The usual thing takes place, trans auto Phosphorylation occurs and the receptor is then phosphorylated. Then it interacts with something else. * Change “several adapters” to one particular adapter called GRB2. GRB2 forms a complex as a sort of sandwich between an activator receptor, a molecule called SOS and SOS relays the signal to this protein that is very important called Ras which is a monomeric G protein. Just like the other G proteins that were heterotrimers this one cannot be active unless it is bound to GTP. Figure 15 – 17 shows one of the ways that a ligand bound to its receptor can interact by means of an adapter protein, GRB2. Here is the sandwich between the receptor and SOS which defines the function of GRB2. SOS is a member of the family of proteins called GEF that is guanine nucleotide exchange factors which exchang GTP for GDP on the Ras G protein. Ultimately, the ligand binding. that is the growth factor, is going to activate the molecule called RAF through RAS. At the top of figure 15 – 20, at step number 4 what happened is that RAS has become activated and this then begins to initiate what is called the mitogen activated protein kinase cascade or MAP kinase cascade. A mitogen is a generic term that stands for any substance that stimulates mitosis. What happens first is that this protein called RAF is activated and as you can see it will enlist a kinase that has a target protein called MEK which it is going to phosphorylate and become active as a kinase and phosphorylate a protein called ERK and make it active. ERK in the phosphorylated form is referred to as the map kinase MapK. The kinase that activates it is known as the map kinase kinase MapKK. And the kinases that activates it is known as the map kinase kinase kinase MapKKK. Several phosphorylation steps take place and in the end we have an active map kinase which moves to the nucleus. When it moves to the nucleus it try to find its targets some of which are transcription factors. Those transcription factors are activated which increases the binding for their target genes and those target genes are primarily involved in the growth responses. This is how the cell cycle is stimulated by the binding of an external growth factor through the map kinase cascade. Under most circumstances, for a particular cell, it shouldn't be always in the “on” position. Evolution dictates that one of the genes that is also activated by the map kinase cascade is one called MKP for map kinase phosphatase. Basically it provides a feedback signaling molecule mechanism to terminate the activity because it takes the phosphate group off the map kinase and inactivates it. There is stimulation for a while, the map kinase cascade gets rolling, but one of the products of that pathway is a feedback inhibitor which turns down the expression of the pathway. The map kinase cascade is not just involved in cell proliferation but rather in a variety of cell types, in a variety of organisms, it can have many different functions regulating normal cellular behavior in homeostasis, or some aspect of development. You might guess that there are a number of map kinase components. In mammals there are 14 different map kinase kinase kinases, 7 different map kinase kinases, and 13 different map kinases. It depends on who is present and what their targets are. That is, it depends on which one is present, how they interact and what types of molecules they phosphorylate and what the activities of those molecules are. This combinatorial control provides a means to generate different responses from a variety of signaling molecules. So that is the map kinase cascade and the end of the formal discussion of the receptor tyrosine kinases. Now we will talk about interactions between signaling pathways. These interactions happen in a couple of different ways. There is something called convergence where two things come together. This is when two different stimuli in the beginning let's say that then activate pathways that share common downstream effector molecules. There is something called divergence that is a single stimulants that can goes in two different directions that is it activates more than one type of signaling pathway. Lastly there is something called cross-talk that is the products of one particular pathway have an effect on the products of the second pathway. Figure 15-31: convergence example: shown in blue is the plasma membrane, in this particular case what this figure shows is a G protein coupled receptor at one part of the membrane, here is a RTK molecule in the same cell but different part of the membrane, both of them are bound to their activating ligand molecules. Both of those pathways, both activating receptors are activating the signal transduction pathways but these two converge on the phospholipase C molecules. That is, both pathways activate a different phospholipase C so what happens then is that IP3 and DAG are going to be produced, calcium is going to be released and its going to do whatever its supposed to do in each circumstance. An example of divergence here is one which the activated receptor tyrosine kinase at the bottom activates three distinct pathways. The one we talked about, phospholipase C and two other pathways that are actually then going to converge along with calcium on cellular activity in mitogenesis. That is they are going to stimulate cell division. An example of crosstalk in this particular situation is the calcium effect. What happened is the production of calcium by the first pathway involving phospholipase C, is effecting some of the products and activities of the other pathways. This is a generic example of convergence, divergence and crosstalk. An example of convergence in figure 15 – 32 shows that you have three different signals coming in and all three of them are giving the signal to the map kinase cascade to be active. So whatever the signal was to begin with, all of them are telling the cell to move towards cell division and this gives a strong Ras signal which gives a strong map kinase cascade. Which then ultimately results in cell proliferation. The one on crosstalk is figure 15 – 33. What you see at the top is a plasma membrane with two different receptors molecules. One is a growth factor and one is for epinephrine. They are each going to initiate signaling cascade but without protein kinase A, that is PKA, RAS is going to activate RAF and that will activate the map kinase pathway. What happens in a situation where you also have epinephrine, the protein kinase a comes in and phosphorylates Raf and that inactivates or stops this pathway. It stops it from signaling to the map kinase pathway so that cascade is not activated. The most important slide for today's lecture is the combination of positive and negative influences that determine the appropriate responses of a cell. Here is my generic cell; it has only three types of receptors in its membrane. One of the receptors is red and if the red receptor gets activated, it will initiate a signaling pathway where there is a metabolic change that occurs in the cell. The second pathway comes from the two blue triangle receptors at the top. When this receptor is activated it will initiate its pathway and ultimately that will lead to cell proliferation, that is, it is a stimulus for the cell to divide. The third receptor, if it gets activated, something very bad will happen. That is, it initiates the pathway for programmed cell death. So two very opposite pathways going on. One telling the cell to initiate cell division. The other telling it to kill itself. If all three of these are activated at the same time what might happen? Let's make up the following. Supposed that the product of the first pathway involved in metabolic changes are also inhibitors of some of the products of the second and third pathways. This will tone those two pathways down. Suppose one of the product of the second pathway also inhibits the third pathway. The end result in this particular case is, if all three signaling pathways are active, then proliferation is going to be inhibited, that is you inhibit this molecule that is charging this particular function, survival is going to be promoted that is you are giving a double stop signal to the pathway that tells the cell to commit suicide and the metabolism is changed in someway. Under a particular set of circumstances, you are not to getting cell death or cell proliferation, you are suppressing those pathways, changing the metabolism of the cell for the short-term, so you cope with those conditions and of course when the conditions change, the situation will change. The next thing that might happen is that the cell might begin to divide or the cell initiates the suicide signal. This is the complex part. This image is to give you some perspective on how complex things could get and to admit that of course scientist who think they are very smart don't really know much at all. These are the things we know about but imagine the things that we don't know about and how these things are connected to one another. There are Map kinases in several places and you might see some other things that we've heard of. You might not have thought that one thing could be influenced by so many other things in the cell. There are lots of different places where interactions can take place and it depends on the sum of those things to keep you from going insane. All cells are exposed to numerous signals. These signals change second by second, minute by minute, hour by hour, and may be very different from one day to with the next. Some cells don't respond. There are a lot of signals out there but you can't possibly respond to all of them and it's not appropriate to respond to all of them and that is why Mother Nature created receptors and groups of clusters of receptors that exist in different cells. If you can't see the signal you can't do anything about it unless you can receive the signal with a receptor. Now many receptors can be active in a single cell type each initiating its own signal transduction pathway. The pathways response depends on which factors are present, which adaptors are present, which kinases are present and phosphatases are present. What their targets are and if they are present and how much are they. The response depends on the sum of the positive and negative influences of the signaling molecules and the integration of those signals into a particular reup the cell can define and make appropriate adjustments in its metabolism to finely tune the response. There are few examples where there is something important to memorize but there are lots to keep in mind about simplifying what is going on in the figures. Now let's talk about Apoptosis. Apoptosis means programmed cell death. Apoptosis occurs in the context of development as well as in the cleaning up damaged cells. One of the best known examples is that of the human limbs. What you see here is that 36 days after inception, a little hand is formed and 48 days it becomes more obvious that this is probably the hand of a primate. You can see that the digits are beginning to get more defined but if you look closely you can see that it looks quite webbed. There is skin between the digits that you can easily
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