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The PI3K AKT mTOR pathway and cancer Part 3 with English subtitles  

okay so welcome back to this next video

in which we are discussing the pi3

kinase a KTM tour pathway and its

involvement in cancer okay right so

we've discussed that type 1 pi pi

3-kinase azhar heterodimers which

consists of a catalytic subunit and a

regulatory subunit ok and the catalytic

subunit there are four different

possibilities which are called the pr

hundred and ten proteins okay so there

is PR hundred ten alpha pure hundred

tembisa kiya hai Nguyen Tan Gama and PR

hundred ten Delta okay and these are

coded for by genes which are called

pik3ca catalytic subunit and then you

have the corresponding Roman alphabet

letter for the Greek alphabet letter

here so a alpha beaver beta G for Ghana

and David elta okay right we then

discussed that the type 1 pi3 kinase is

named after what catalytic subunit it's

made out of so there are P I free kinase

alpha beta gamma delta corresponding to

the four different catalytic subunits

that you can use to build your type 1

pi3 kinase okay and we then discussed

that the type 1 pi3 kinase enzymes can

then be further divided into type 1a pi3

kinase enzymes which are the pi3 kinase

alpha beta and Delta and these ones are

all going to have certain regulatory

subunits that combined to them and this

regulatory subunit is also going to be

able to bind to receptor tyrosine kinase

errs and therefore the years pi3 kinase

is the type 1 pi3 kinase is there going

to be activated by receptor tyrosine

kinase is meanwhile at the type 1b

geography kinase is including only pi3

kinase gamma that has very different

regulatory subunits which combined to it

as we'll discuss and those regulatory

subunits aren't capable binding to the

receptor tyrosine kinase and therefore

type 1b pi3 kinase is aren't activated

by receptor tyrosine kinase

so let's now turn our attention on to

the regulatory subunits of whiskey I

free kinase is then okay so let's start

off with the regulatory subunits that

can be used in type 1a pi3 kinase s so

remember if we're making a type 1a pi3

kinase that means that we've highly used

PR hundred and ten alpha PR hundred ten

beta or PR hundred ten Delta to create

pi3 kinase Alphabeat or Delta okay right

so the regulatory subunits that can be

attached to these catalytic subunits are

called p85 type regulatory subunits okay

and there are three different genes

which could be used to make these p85

type regulatory subunits and one of

these genes has free different splice

variants so let me firstly tell you the

nails of the genes which make the p85

type regulatory subunits and then I'll

tell you the names of the proteins which

they can produce okay right so the genes

for p85 type regulatory subunits are

called pik again and eve of the free and

now are for regulatory subunits OPI k 3

is 4 pi 3-kinase are for regulatory

subunit okay and then you've got our one

then you've got Pik free r2 and Pik free

are free so there are these free genes

which code for p85 type regulatory

subunits which are the type of

regulation subunit that can be attached

to p110 alpha pm10 vita or p element n

delta which the catalytic subunits in

these type 1a pi3 kinase is okay right

so Pik free are one has three different

splice variants that it can produce and

these three different splice variants

have very different molecular weights ok

so the free different splice fans that

can produce are of 85 k the Daltons and

the

is called p85 and then you put an alpha

there to show that it's from this type 1

regulatory subunit gene okay it can also

produce one of 55 k the Daltons called

p55 alpha okay again the Alpha denotes

that's from this r1 gene okay and then

find it can produce one of 50 kinna

Dalton's which is called p50 alpha so

those are the three different regulatory

subunits that are all p85 type

regulatory subunits and can all be

dimerized with these free catalytic

subunits and they're all created by this

one team pik free r1 and a free

different splice variants of Pik free

are one okay right then for the gene pik

three are to this only has one splice

variants okay and again it weighs 85

killer Dalton so this is P 85 ok because

it's coded for by the seculars Union we

put a bit of that ok so pH 5 beta is an

85 to the Dalton regulatory subunits of

a pi 3-kinase made by this pik free are

two team again it's the only one that's

made by that gene finally the pik free

are free gene that makes a regulatory

subunits of 55 killer dalton molecular

weight called p55 gamma ok so these five

different proteins here p85 our 4p 55

our 4p 50 alpha p85 beta and p55 gamma

these are the p85 time regulatory

subunits which can be bound to one of

these catalytic subunits here to make a

type 1a pi3 kinase ok so to summarize

here when we're building one of these

pi3 kinase heterodimers and we want to

be able to type on a pi3 kinase you put

a peer hundred and ten subunit here and

that will either BP 110 alpha beta or

delta and then you put

ap 85 type regulatory subunit here and

that will be one of these five proteins

here I other p85 alpha p85 beta p55 gala

p55 alpha or p50 and alpha okay so one

of those five again that's often how

people will show it in little cartoons

i'll just show p85 in a box to denote AP

8520 regulatory subunit and then p 110

in a box to show a p 110 type catalytic

subunit okay right now let's talk about

the class 1b or the type 1b pi3 kinase

this okay just remember the type 1b pi3

kinase is they had as their catalytic

subunit always p 110 gamma okay now they

have different regulatory subunits okay

so peel huntington gamma does not bind

to the p85 type regulatory subunits okay

it has only two regulatory subunits that

it combined to and these are called p101

okay and also p 87 so it has two options

for what it combines we can either buy

them too p 101 or a combined 2p 87 and

these are coded for by different genes

so p101 is encoded by pik three are 50 k

and p 87 is a coded for by pik free are

six i don't quite know what happens a

pik free are for ok these are coded for

by pik free are five and pik three are

six okay right so if you want to be able

to type 1b pi3 kinase you don't have any

choice about the catalytic subunits okay

so if we draw this heterodimer here to

have any choice about the catalytic

subunit that is forced to BPI engine

tank downer but you do have a choice in

the regulatory subunit it can either be

PR 101 or it can be p 87 there okay and

that

a type on BP I free kinase enzyme okay

right now before we look at the

structure of these regulatory subunits

and catalytic subunits have been a bit

more detail don't worry we're not going

into into too much detail we're only

going it into it into the detail that

we're going to need for some of the

later comments I want to be able to make

okay and before we go on to that let me

just say something about the expression

profiles of these different types of

type 1 pi3 kinase enzymes okay so

basically you find pi3 kinase alpha and

pi3 kinase beta type 1 pi3 kinase is all

over the body okay so these are

expressed pretty much everywhere in all

cells of the body you're going to find

pi3 kinase enzymes where the catalytic

subunit is p110 alpha or PR engine 10

beta and the regulatory subunit is

therefore a p85 type regulatory subunit

whereas in contrast the pi3 kinase gamma

and pi3 kinase Delta enzymes are much

more selective in where they are

expressed okay they are generally found

in white blood cells okay we're going to

find this is very significant later on

for leukemia ok so the major drug that

has had success so far as in blocking

this pi3 kinase akt m12 is used to treat

chronic lymphocytic leukemia and the way

actually works is by inhibiting pi3

kinase Delta so we'll talk more about

that drug later on it's called an idol

elizab ok but we'll come to that later

on that's the major success story that's

spurring on more research into drugs

which inhibit pi3 kinase there Katie end

war pathways ok right so pi3 kinase out

from visa they're found everywhere pi3

kinase Cameron tell so they're much more

selective and whether expressed just in

leukocytes white blood cells leukocytes

is just the fancy term for white

sells wbcs okay right so let's now look

at the structure then of type 1 pi3

kinase subunits and a little bit more

detail so the first thing I want to talk

about is the structure of one of these

type 1a catalytic subunit subunits in

more detail so I want to look at p110

alpha P a hundred and ten beta and PR

engine 10 Delta okay we're just going to

look at its primary structure so we're

going to see some of the key domains the

PIAA hundred ten alpha be trimmed out to

have and we're going to see the

importance of certain of these domains

later on in the video okay so for now

here is the amino terminus of the pr

hundred ten alpha beta or delta protein

okay and the first important main that

you have are in the protein is what's

known as a p85 binding domain and this

is the domain which is used to bind to

the p85 type regulatory subunit ok so

this for short is just abbreviated to

p85 bd4 p85 behind in domain okay so

i'll show you the portion on the p85

type regulatory subunit later this

actually binds to that p85 finding the

name okay then after the p85 binding

domain what you have is the main it's

known as the rouse binding domain ok and

r BD and we're going to see the

importance of this later on ok when we

want to discuss the activation of piano

free kinase enzymes by small gtpases one

of the key small gtpases that is capable

of activating many p I 3-kinase enzymes

is raz okay so we'll come back to this

as well so this is aroused by linked

moon so i'll just write that one out

for so the r is for razz okay then the

BT I'll just abbreviate down to BD

binding the name ok right then after the

rouse binding to me you have a domain

that's found in many different proteins

called a c2 domain in our see two

domains are generally found in proteins

that bind to calcium and are activated

by calcium so for instance is very

important in protein kinase C enzymes

okay what its importance is in the

catalytic subunits of PR hundred and ten

while catalytic subunits of pi3 kinase

enzymes isn't fully no not yet okay so

there's a c2 domain then what you have

is a helical reach and made up of alpha

helix ease okay so this is a helical

portion here and then following the

helical portion you then have the actual

catalytic domain of the catalytic

subunit so just to reiterate again this

is the primary structure of a either p

110 alpha p110 p2p 110 Delta ie the

catalytic subunits of type 1a pi3 kinase

enzymes okay so there's the helical

domain and then here in vivid purple

that's the catalytic domain of this

catalytic subunits this is the domain

that actually catalyzes the

phosphorylation of pip2 into pip3 okay

so that's the domain primary structure

of a type 1a catalytic subunit of pi

3-kinase ok now obviously it would be

forwarded up in reality it wouldn't be

linearly like this okay but that shows

us some of the important domains that

we're going to need to understand when

we want to discuss the activation of

these later on okay right so that's the

structure of the domain structure of PR

hundred ten hour for PR in tembisa and

PR hundred ten delta the next thing i

want to make a comment on is how is p

entertain gamma than differently

what's not hugely different all that

differs between pm10 alpha beta and I'll

champion tan gamma is that you have lost

this p85 binding domain okay so that's

important because that now means that

the pier hundred ten gamma cannot bind

to the p85 type regulatory subunits so

basically if you wanted to draw PA

hundred ten gamma just get rid of this

bit scrap this okay start the amino

terminus there and just have these

portions here that will be peer hundred

ten gamma here okay right the next thing

I want to comment on is the structure of

a p85 time regulatory subunit because

this is actually known ok we have

crystal structures of what the free

dimensional structure of this looks like

ok now we're not going to look at the

three-dimensional structure of it we're

just going to look at its domain primary

structure ok but that's an achievement

because we don't have that for the p101

over PA 87 yet ok so I'm not going to be

able to show you what the main structure

of these two is but I can show you what

the de main structure of users now this

is where it differs depending on what

size you are ok so the p85 ones are

longer than the p55 ones and the p51

again these have additional domains that

these free don't so pH 50 mph 5 feet are

bigger they have more domains than key

55 and p50 ok but p55 and the p50 they

have all the same important domains

obviously p50 is going to be smaller but

it doesn't lack any of the important

domains that p55 al from p55 damn i have

ok so we can summarize those two

together so I think I'll go down here to

show you the structure of a p85 time

regulatory subunit ok so this first

portion that I'm about to put here this

obviously isn't essential for the

function because this is the portion is

only going to be there in the p85 our

friend the p85 beta but not the smaller

ones ok right so this first

consists of an SH freedom and you know

can lot of heavy thing mr. main found in

a huge number of different proteins it

stands for sarka mala g freedomain

because it was first found in the non

receptor tyrosine kinase Sark okay so SH

free then after the SH free what you

have is a protein rich domain which I'll

just abbreviate as key here so it's a

prone enriched name okay I'll just put a

few labels here so SH free stands for

Sark homology ok so the S is for Sark

anxious for homology and it's the star

ecology free domain we're going to see

another example the song homology domain

in the moment that's going to be more

important for the function of the pac-5

subunit ok this Peter name here this is

a pro knee richd main Salim has a lot of

pro name residues within it ok right

then the final name that's in this

little extension out the front that you

have in p85 hour from p85 betta but not

in the other three is what's known as a

breakpoint cluster homology the money ok

be aged men which I'll coloring in blue

here ok so the H stands for break point

cluster homology domain and again it's

the domain that you find in many

different proteins and the function of

it here isn't fully understood yet ok so

breakpoint cluster homology domain right

so those are the three domains that you

only have in p85 alpha and ph 5 visa but

not in the final three so those can't be

essential for the function as a

regulatory subunits of pi3 kinase

catalytic subunit okay right so now we

start the essential bits and these are

present in all five of them okay so if

we were talking about one of the smaller

ones such as p55 alpha p55 gamma or p50

alpha okay so p55 alpha p55 gamma

and p50 alpha they would start now

they'd have their amino tennis hear how

they have all the bits that I'm about to

tell you about ok so again I'll stress

the point that although p50 alpha is of

course going to be smaller than p55

alpha it doesn't matter Kenny of the

important domains as Pete that p55 a

half a house okay and that's why as far

as my very simple domain structure

picture is concerned they're going to

look the same basically ok right so now

what we have is another protein rich

domain so this breakpoint cluster

homology domain is flanked by two

protein-rich domains in the p85 alpha

and the PFA 85 beta in these smaller

ones the protein rich domain is the

first domain that you have in this p85

time regulatory subunit ok then what you

have is two sh2 domains split by a

domain sits in between them called the

inter sh2 domain ok so this one will

call the N sh2 domain all that means is

the n-terminal the one that's closer to

the n-terminal and then sh2 again it's a

really famous type of domain Sock'em

ology to domain ok again the domain is

found on a huge number of different

proteins named after the fact that was

first found in the saab non receptor

tyrosine kinase but have since been

found in loads of other proteins ok so

this is a scientology to domain and this

is what we're going to call the end sh2

domain simply because they were going to

be two of them and this is the one

that's close to the end terminus okay

now start kamala g22 names are really

important in binding to phosphorylated

tyrosine residues on for instance

receptor tyrosine kinase is that been

activated and indeed this is going to be

what the important function of this is

that it's going to play an important

role in the activation of the pi3 kinase

enzyme by receptor tyrosine kinase it

okay then what you have is a domain

called the inter sh2 domain so this is

that's an sh2 domain this is standing

for the inter sh2 domain so is h2 here

stands for inter sh2 domain arrow can it

actually consists of two alpha

Hennessy's that end up folding back on

one another and coining into a

coiled-coil demand okay right so that's

the domain sitting in between the N sh2

domain and the final important main of

this p85 type regulatory subunit which

is the c-terminal sh2 domain the sea sh2

domain here okay again this is another

psychology to domain and because it's

the one that's near Alice c-terminal

it's called the c-terminal sh2 domain ok

right so these are the two really

important mains here in these p85 time

regulatory some excuse me something

that's these are the ones they're going

to bind to phosphorylated tyrosine

residues ok so again I'll reiterate a

point that if you are one of these

smaller types of p85 type regulatory

subunit either p55 alpha p55 gamma or

p50 alpha then you're just going to

start here and you're just going to have

this protein rich domain then you've got

these two sh2 domains an n-terminal and

c-terminal sh2 domain with the intern

sh2 domain in between them ok now the

next important thing I should tell you

is how does the pac-5 type regulatory

subunit binds to the type 1a catalytic

subunit ok what's through an interaction

between this interesa to domain here and

the p85 binding domain here ok remember

again we've drawn them as minier primary

structures in reality they be afforded

structure again this does resemble blob

when it folds up ok so it's certainly

not a great big long protein like we've

drawn as it folds up into a block okay

right so in fact these pictures are a

little bit more accurate really and what

they actually look like ok but it's

through the interaction

the interest h2 domain that the

catalytic subunit PR hundred 10 alpha

pm10 beta or PM 10 Delta binds to the

p85 type regulatory subunit okay right

so those are the structures of pi3

kinase subunits in more detail again as

I say we've done that so that when we

want to come on to discussing things

like how they are now activated and how

well mutations later on where mutations

are we have these domains and we can

point at where they actually asked that

we we're not just saying or when this is

in the helical domain we actually know

where that is in the protein okay right

so we'll call it for this video and in

the next video what we'll turn our

attention on to is the mechanism by

which pi3 kinase enzymes type 1 pi3

kinase enzymes are actually going to be

activated so we'll see that they can be

activated by G protein-coupled receptors

they can be activated by receptor

tyrosine kinases they can add to be

activated by small gtpases and then

after we discuss their activation will

then see Worf the generation of

spattered on inositol 345 trisphosphate

in the cell membrane is going to do and

that will lead us on to the rest of the

pi3 kinase akt and tour pathway

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