Welcome back to bio signaling on catalyst University my name is Kevin toka please make sure to like this video and subscribe to the channel for future videos and notifications alright in the previous set of videos we talked extensively about the g-protein coupled receptor in this video we’re gonna switch gears and talk about a new kind of receptor and.

That’s what’s the called the receptor.

Tyrosine kinase usually abbreviated RTK.

And the classic example that’s used in most textbooks for signaling molecules that activate this kind of receptor is insulin which we all know is a pancreatic.

Hormone released by its beta cells that causes glucose intake into most cells and the question.

Is how does the RTK work well first of all let’s break down the name first of all it’s a receptor and apparently this receptor has tyrosine residues on it and it’s a kinase now what does this receptor is going to do is it’s actually going to.

Do what’s called Auto phosphorylation some texts may call this cross phosphorylation and so here’s what happens you see here the insulin receptor in the membrane now you see there’s actually two components there’s one over here on the right and then here it hears its mirror image on the left initially those two receptor units are separate so maybe the right ones over here and.

The left one is over here they’re separate they’re not.

What happens is is when insulin comes in and insulin actually comes in as a dimer believe it or not insulin actually is going to probably bind to one of them maybe the.

Left one first and then it’s going to kind of move in the membrane and recruit the right one and so initially those two receptors are separate but.

When insulin binds they kind of get closer and closer together until finally they dimerize and this is actually a homodimer because both of these are exactly the same okay and when the insulin receptor dimerizes that’s when it becomes activated in fact that’s when any RTK becomes activated they dimerize in the presence of the hormone or whatever the signaling molecule is okay now when they dimerize that’s what induces Auto phosphorylation so what is that well on the cytoplasmic domains of each of these receptor units the left and the right one there is what we call.

A tyrosine kinase and so what happens is the right one let’s say the right tyrosine.
Kinase will phosphorylate tyrosines.

On the left unit but then the left one is identical so it’s tyrosine kinase activity will phosphorylate tyrosines on the right unit and that process is called auto phosphorylation and so whenever enough of these tyrosine residues on each of these different insulin receptor units are phosphorylated.

The receptors fully active now what the insulin receptor can also do is it can also phosphorylate tyrosines.

On other proteins and the example here is IRS one so IRS one is going to come over here and the RTK is gonna phosphorylate it and so you see over here the product IRS one with several phosphates attached now without getting too much into the weeds of this the basic idea is that IRS one is going to activate another protein which is gonna activate another protein which is going to activate another protein and so on and so forth and they’re kind of gonna form a chain a physically connected chain whose goal.

Is to activate RAF one okay so here’s what we have IRS one only when it’s phosphorylated binds and activates.
Grb-2 okay and it stays connected to GRB.

2 and then GRP two binds in activates SOS which for some reason is called son of seven lists I’m not sure what the origin of that name is but it’s SOS an SOS becomes activated then we have another g-protein here this g-protein which is sin to what we saw in the g-protein coupled receptors earlier but this G protein is.

Called wrasse it actually has a name to function just like in the case of any G protein it has to.

Have bound GTP but in any case if it has bound GTP and it comes in contact with SOS it gets bound.

It becomes activated and then raf 1 if it comes in contact with wrasse Rath one becomes activated and so what we have here is essentially kind of the thing where it’s like the foot bones connected to the anklebone which is connected to the shin bone connected to the knee bone connected the femur the hip and so on and so forth and so we have a chain of proteins that ultimately are connected and become.

Activated so irs-1 is the first one which.

Is connected to and bound to grb-2 which is bound to SOS which is bound to rass and then which is bound to raf 1 and the whole goal of this little chain right here is to activate raf 1.

Ok and raf 1 is a kinase it’s actually the first kinase that we come across in this chain right here that’s important so raf one can phosphorylate another protein it can phosphorylate mek okay so raf one phosphorylates mek you see.

Here mek come in and it becomes phosphorylated when mek becomes phosphorylated it becomes activated and it itself is a protein kinase so when mek is activated you see here.

At phosphorylate erk so Earth comes in here it gets phosphorylated by mek and you see now ERG has a couple of phosphates on it now when Kirk gets activated it itself goes into the nucleus and it phosphorylates some transcription factors so it’s specifically a phosphorylated transcription factor called elk 1 and when elk 1 becomes phosphorylated it dimerizes with another transcription factor called srf and they.

Bind together in a heterodimer and they can bind to DNA in certain regions and induce transcription meaning they up regulate certain genes.

That are involved in insulin type of functions ok so for example what’s one thing that insulin does insulin promotes the sin the sis of glute 4 receptors in muscle membranes so.

Perhaps the gene that’s being transcribed here is the gene for the glute 4 channel okay for it to getting glucose into cells alright so that’s the basic idea so again there’s a lot of weeds here so to speak but the idea is that insulin binds to the insulin receptor and RTK it causes two units of it to homodimer eyes and when they do they become activated and they undergo Auto phosphorylation they phosphorylate their partner RTK unit and then you.

Have full activation of the rtks when that happens they can then phosphorylate a protein like irs-1 which then initiates a chain of proteins leaving the activation of raf 1 this chain here in the case of the insulin receptor which is very well studied you have irs-1 grb-2 SOS rasa g.

Protein and rath one then raf one is.

A protein kinase it phosphorylates and.

Activates mek mek is also a protein kinase so when activated it phosphorylates and activates Kirk Kirk is also a protein kinase so when it’s phosphorylated it goes into the nucleus this time and then.

Phosphorylates a transcription factor which activates it leading to up regulation of genes involved in insulins function okay and that’s the.

Basic idea of rtks and this pathway the.

Proteins may change a little bit but in general it’s pretty much all the same regardless of the molecule it’s doing the signaling which in this case is insulin now one thing I’ll just mention that’s kind of a common thing about rtks generally speaking the molecules that bind to rtks are almost always growth factors not always but a lot.

Of cases they are so for example epidermal growth factor binds via a receptor tyrosine kinase I believe insulin-like growth factor also binds via the same receptor and like I said most of.

These proteins and here are the same now being growth factors if you ever had this insulin receptor or any aspect here.

Get out of control what might happen the answer is cancer in fact there’s actually different mutations in proteins within this pathway.

But actually when they go haywire you actually get uncontrolled cell growth considering the fact that most of these things that bind including insulin.

Are growth factors themselves one of the most common proteins in that’s implicated in cancer in this pathway.

Is actually Rast now in one of the previous videos we talked about G proteins and G proteins are only active when they have bound GTP when they have bound GDP down here they’re inactive and g proteins all of them have an intrinsic.

Which means that if they hydrolyze that gtp into GDP they become inactivated well like any g-protein Rass has an intrinsic gtp ace activity but it’s a little slower than most G proteins it’s not very efficient at getting rid of that gtp so if you combine that already kinetically slow gtp ace activity with a mutation then.

Not really ever going to get rid of that gtp it will eventually but it’s gonna be very slow and what would happen in that case if it can’t get.

Rid of this gtp all wrasse will continue continue to remain bound and activate raf one what happens if raf one remains activated then this entire transcription goes up and up and up and it keeps going and going going and you get more and more transcription of all these insulin related genes and essentially they just don’t stop.

And that is one of the pathophysiological aspects that leads to cancer if you have a mutation in Raths and considering the fact that wrasse.

Is not only involved in insulin but also other growth factors and rtks as well you can see why a mutation and this protein would tend to cause cancer.

Alright so hopefully this video gave you a little bit of intuition on receptor tyrosine kinases in the next few videos.


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