okay so welcome to this next video in which we're discussing uh the vogelstein model of colorectal carcinoma so so far what we have seen is uh that uh it starts the whole process begins with a single uh colonic epithelial cell which happens to get two mutations in both of its well a single mutation in both of its apc genes so it loses function in both of its apc genes that means that the beta catenin destruction complex is no longer functional because there is no adenomatous polyposis coli protein which is an essential part of the beta
catenin destruction complex okay so the beta-catenin destruction complex is no longer functional so it no longer phosphorylates uh beta-catenin if b-ticketinin doesn't get phosphorylated let's have a look over the other side if beta catenine doesn't get phosphorylated then it doesn't get ubiquitinated and it doesn't go to the proteasome so b nicotine builds up within that cell it then acts as a transcriptional co-activator along with the t-cell factors and the lymphoid enhancer factors and this leads to the cell moving from interphase to g1 phase so what happens is this cell that has just happened to be
unfortunate enough to get two mutations one in each of the apc genes this cell is now going to divide far too rapidly basically it's going to divide and then its daughter cells are going to divide and before long you're going to have an entire population of genetically identical cells all of which have no functional adenomatous polyphasis coli now the next process then this at the moment is not a cancer this is an early adenoma it's a benign tumor it's just a mass of cells at the moment it's not do it's not invading and destroying the
healthy tissue which is what cancer does okay so the next process in in forming cancer then of all of these green cells of all of these genetically identical cells which have two apc mutations one of them just one of them it now needs to get a mutation in this gene k-ras so let me remind you of where raz fits into the growth pathways so it's part of the growth factor uh receptor pathway uh in which leads to the map kinase pathway okay so uh let's have a look at our growth factor receptor here so basically
initially our growth factor receptor is in the phospholipid bilayer of our cells so here is our growth factor receptor what color should i color it in we'll have it in orange okay so this is the growth factor receptor here and again it could be complete we're leaving it completely general so i'm not saying which specific growth factor this is this is just a growth factor receptor okay right what's going to happen next is that the growth factor when the growth factor is released onto the cell what it will cause the change in conformation in the
growth factor receptor and that change in conformation will allow uh two growth factor receptors which have both undergone um the change in confirmation process to dimerize so let's show that so they change confirmation so that's what i'm showing here it's now got growth factor bound to it which i will show in green here so this is growth factor in green and in orange now the growth factor receptor which has bound to its growth factor and it has now changed conformation and this change in conformation will allow it to dimerize so this here is the growth
factor and again it's completely general i'm not saying which specific growth factor it is it could be many different ones what's important is that they all share the same downstream pathway and kras is part of this downstream pathway so then what happens is this gets together with a body basically another growth factor receptor which has bound growth factor and has changed conformation which now allows it to dimerize so they dimerise together like so okay so he's in this here's another growth vector molecule bound to the um extracellular domain of this growth factor receptor here okay
right then what's going to happen is a process known as autophosphorylation okay so another name for these growth factor receptors is that they can also be called receptor tyrosine kinases and the reason they can be called receptor tyrosine kinases is that each one of them has in it a catalytic domain which is capable of phosphorylating tyrosines so both of these growth factor receptors has a tyrosine kinase basically okay and basically what will happen is when they dimerize like this let's call this growth factor receptor here growth factor receptor one and this growth factor receptor here
growth factor receptor two what will happen is that the tyrosine kinase of growth factor receptor one will phosphorylate tyrosine residues on growth fat receptor two and grow factory receptor two's tyrosine kinase will phosphorylate the tyrosine residues of growth factor receptor one okay so let me just briefly remind you audrey my poppy is falling off it's remembrance day and that's for them off sorry about that uh right so uh let me just remind you briefly of the structure of um a uh tyrosine amino acid so here's the amino terminus here so we're just drawing the basic
structure generic structure of the amino acid let me just deal with this pin there we go over there right so here's the amino terminus of the amino acid or the amino group of the amino acid here's the alpha carbon of the amino acid here's the hydrogen off the alpha carbon and here's the carboxyl group of the alpha carbon as well okay now the r group in the case of tyrosine is you have a methylene group here and then you have a benzene ring off that methylene group like so okay and then off the benzene ring
you also have a hydroxide group so this is the structure of tyrosine now uh basically what can happen is you can phosphorylate the uh hydroxyl group of this tyrosine um tyrosine r group basically so if i draw the structure of phosphate group a phosphate group consists of a phosphorus atom double bonded to an oxygen up there a hydroxyl group off this side and a hydroxyl group off this side and it also has a single bond with another oxygen which has acquired an additional electron via an ionic bond and what can happen is that this hydrogen
of this hydroxide can leave the hydroxide of the phosphate can leave as well and then this oxygen can then bind to this phosphorus atom here and form a link that hydrogen and the hydroxide can then form a water molecule so the reaction basically produces a water molecule it's therefore known as a condensation reaction okay so tyrosine kinases can phosphorylate tyrosine residues now the intracellular aspect of each of these receptors has a lot of tyrosine residue so let me denote them just here basically okay and what can happen is that this receptor also somewhere in it
has in uh has a tyrosine kinase so the tyrosine kinase in receptor one so i'll put this maybe here can phosphorylate the tyrosine residues of receptor two so let me just denote the tyrosine at the phosphorylation uh by pink dots basically so it's adding these phosphate groups onto these tyrosine residues then the tyrosine kinase of receptor two can then phosphorylate the tyrosine residues of growth factor receptor one so you get these phosphorylated tyrosine residues on the intracellular aspects of these receptor tyrosine kinases or these growth factor receptors then what happens in um the map kinase
earth pathway and i want to stress that growth factor receptors can have loads of different downstream pathways which they interact with but brass is specifically involved in the map kinase irk pathway so we'll focus on that one uh basically what happens next is there's another protein known as the growth factor receptor binding protein two which i'll denote in this new green that i found so this is this new green here oh it's sort of a turquoise color right so there we go this is the first time that protein has appeared that color has appeared in
my videos so it's being used to denote the growth oh dear and i've written graph again growth factor um receptor binding protein to binding protein two and i should write try and write as clearly as possible rather than writing this sort of crammed up little style right so uh growth receptor binding protein two is often denoted g r grb2 for short okay so they took the growth they took the receptor they took the binding and then they took the two grb2 right when grb2 binds to the phosphorylated tyrosine residues on the intracellular aspect of the
growth factor receptor then another protein can then bind on top of it and this protein is called sauce okay so here is sauce and sauce i will denote in another new color that i've got which is this purple color so sauce is in purple okay and when sauce binds to the growth factor receptor binding protein 2 it becomes an active enzyme it activates that and the role of sauce is to convert raz gdp and raz basically is a g protein a monomeric g protein and now we're talking about a specific grass so before whenever we've
talked about the growth factor receptor pathways we have kept ras completely general but there are loads of different types of ras and k-ras is a specific raz protein okay so now we'll talk about k ras now it does exactly the same thing as i showed with the generic raz proteins in my in my videos on uh growth fact on the map kinase pathway and um basically it binds gdp and when it's bound to gdp it's inactive okay so we'll denote k-raz in blue here and this again is a new highlighter so here is k-raz in
blue okay and whilst it's got gdp bound as in the case of all g proteins when they're bound to gdp they are inactive so what sars does is it converts the cr k ras uh gdp into k raz gtp so it chops off this gdp and binds instead gtp onto the k-ras okay so you have activated this monomeric g-protein which is k-ras so you've got k-ras gtp now okay and what k-rash gtp is going to do is it's going to activate another enzyme known as raph kinase so so far to summarize the whole pathway which
is something we're always taught in medicine summarize in patient interviews so growth factor binds to the growth factor receptor it changes the confirmation of that growth factor receptor to allow growth factor receptors to dimerize they dimerize the tyrosine kinases in these receptors phosphorylate each other's tyrosine residues when you have these phosphorylated tyrosine residues then the growth factor receptor binding protein two combined to those then sauce can mount on top of the growth factor receptor binding protein two and it then becomes active and it starts converting the k rast which is a monomeric g protein which
was in its inactive state and therefore bound to gdp into the active k-ras which is bound to gtp now um i think we'll get another piece of paper before we go on okay right so we've now got k-ras gtp then so let's put this here k-res gtp okay this active monomeric g protein and this is now the point that we've got to in this downstream signaling pathway so growth factor has been put on the cell and it's caused k-ras gtp to go up in the cytoplasm of the cell k-ras gtp binds to another enzyme known
as raph basically it's specifically k-ras binds to a type of wrath known as b-raf okay so b-raf so again just like k-ras is a specific brass protein uh b-raf is a specific rash protein they do the same things it's just different rasp proteins interact with different wrath proteins so in our more general discussion of the uh growth factor um at receptor and the map kinase earth pathway we just sort of generalized we said ras gtp activates a wrath now we're looking at specifics we're looking at specifically k ras and the specific kinase that it activates
is this b raf kinase okay so here we have our active b raf okay so b raph now phosphorylates and activates another kinase enzyme okay so it's going to phosphorylate and activate another kinase enzyme which i'll draw here and the kinase enzyme which it activates is a kinase enzyme known as mech so this at the moment is the inactive mech enzyme so it's not active at the moment and basically it's going to be phosphorylated by this b raf which is a kinase enzyme and it's going to become the active mech when it gets phosphorylated basically
okay so it's now have a phosphate group stuck on the side of it there and it's now active now what color should we denote mechan we'll have it in green okay so bright green is this mech protein now mec has a bunch of names it's also known as the mitogen activated protein kinase kinase so mech enzyme can also be called the watch its full name is the mitogen activated protein kinase kinase i'm meant to be writing as big as possible so it's as clear as possible nitrogen activated protein kinase kinase right okay therefore if you
were to just take the initials of that what you'd end up with as the symbol well there's the acronym for it would be the mitogen activated protein kinase kinase so map kk some people will also refer to that as map for mitogen activated protein kinase and then they'll put 2k to denote that you've got these two k's at the end so if you see it referred to as that don't get confused those are all names for the same thing basically the same enzyme which is being activated by b raf activated by this phosphate group being
added onto it now the nitrogen activated protein kinase kinase is a kinase itself and it is also going to phosphorylate and activate another enzyme okay so the next enzyme in this pathway we'll put here okay and this next enzyme in the pathway is an enzyme known as map kinase so this is the inactivated well the inactive map kinase which is often just denoted map k like that and then when you phosphorylate it it becomes the active map k it's the active map kinase okay and we'll continue this discussion in the next video
