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The PI3K AKT mTOR pathway and cancer Part 2 with English subtitles  

okay so welcome back to this next video

which we are discussing the pi3 kinase a

KTM tour pathway and cancer okay right

so in the previous video what we did is

we went over the basic carcinogenesis

process and we sought an absolutely key

property of cancer cells is that they

over proliferate in fact this is

believed to be the first change the

curse to that somatic cell which starts

it on the progression towards becoming

cancerous okay we then discussed the

involvement of the pi3-kinase aktn tour

pathway in causing a cell to divide okay

we discussed that when a cell takes this

decision to divide firstly it has to

grow and then it was split into two okay

and this requires a major epigenetic

shift basically you have to start

expressing a whole bunch of genes that

you weren't expressing before and I

pregnate expression of a whole bunch of

things that you might have been

expressing before so it causes a major

change in the transcript over and the

proteome of this cell which just means

the collection of all mrnas on a cell

that's the transcriptome and the

collection of all proteins in the cell

that's the proteome okay all right and

we discussed that the way that you

produce this epigenetic shift is to fold

over firstly you have to produce the

transcriptional change you have to now

transcribe the mRNA s okay you have to

transcribe new genes that were being

transcribed before or increase the

transcription of genes that were being

transcribed before that need to have a

transcription altered again this change

in transcription within the sound is

produced by pathways such as the rouse

rats neck Kirk pathway okay which change

the transcription or give a auto

epigenetic control by a transcriptional

control however the pi3 kinase

the mtor pathway that is involved in

translation or control okay so if you

just had the transcriptional control and

just made all of these new mr they's as

a pro division okay it doesn't mean

anything they have to now be translated

into proteins for them to actually have

an effect okay and basically there's

normally a blockade on mrnas that a pro

division being translated as we'll

discuss later on they are also known as

elongation factor 4e sensitive mrna s

okay and there's usually a block on the

translation of these sorts of mrnas okay

so if you now want them to actually be

translated and actually have an effect

on the proteome of the sound you need to

allow them to be translated basically

and that's done by the pi3 kinase a KTM

tour pathway it releases the break on

the translation of these pro division

mrna s okay right so we now want to

discuss this pi3 kinase nkt mtor pathway

and we're going to begin by discussing

pi3 kinase phosphoinositide 3-kinase so

let me just explain how i'm going to

structure our discussion of this pathway

in depth we're going to start with pi3

kinase then we will go backwards and

look at how pi3 kinase can be activated

okay so we're going to look at the

enzyme before we look at how it can be

activated again you might ask well why

not doing its activation before we

discuss its function well because there

are many different ways that pif

recliners can be activated okay it can

be activated by receptor tyrosine kinase

is it can be activated by G

protein-coupled receptors it can also be

activated by small gtp a zit okay so

we're going to discuss the enzyme first

and then go back to its activation oak

and then we'll go on with the pathway

will go on to a katie and then enter

okay right so let's start by discussing

phosphoinositide 3-kinase then so that's

what pi3 kinase

d stands for so pi3k which we've been

writing for so long stands for the P is

for phospho that's the P in a suit I

that's the eye and then it's free kinase

okay so phosphoinositide 3-kinase

enzymes are enzymes which phosphorylates

lipid molecules they phosphorylate

phosphoinositides okay specifically they

phosphorylate phosphoinositides on the

third carbon of inositol ring as we'll

see in a moment okay right now there are

free broad types of phosphoinositide

3-kinase a--'s which are known as tight

warm phosphoinositide 3-kinase its type

2 phosphoinositide 3-kinase errs and

type 3 phosphoinositide 3-kinase is the

ones that we are interested in the ones

that most is known about are the type

warm phosphoinositide 3-kinase errs okay

so we're not going to discuss in this

video at all the type to other type free

phosphoinositide 3-kinase is okay the

three different types of

phosphoinositide 3-kinase is they add

phosphate groups on to the same position

of phosphoinositides but the

phosphoinositide that they target are

very different okay so their substrates

are different type warm phosphoinositide

3-kinase is their substrates are while

their substrate is phosphated I'll

inositol 45 bisphosphate which is often

abbreviated as pip2 okay and this is the

important one in this pathway that

controls the translation of these

elongation factor for really sensitive

mrnas oh in which our pro division mrnas

generally okay so we're only going to

concentrate on type 1 phosphoinositide

3-kinase which have as the substrate

pip2 only so let's now talk about pip2

them because this is going to be very

very important so pap2 stands for

phosphatic

aisle ok that's the P then inositol

that's the eye and then it's for

spattered on inositol 45 this phosphate

so the second p in the PIAA p2 is for

phosphate and then because you've got

two of these phosphates added on to the

phosphated I'll inositol its p 20 in now

if you're being slightly more strict you

would abbreviate this down not to pip2

like so but instead you would abbreviate

it down to pi 45 p 2 okay because this

abbreviation here doesn't actually tell

you which carbons of the inositol ring

the two phosphate groups come off as

this abbreviation does tell you that

they come off the fourth from the fifth

okay now the most important example of a

phosphoinositide with two phosphate

groups coming off the inositol ring is

this one where they come off the fourth

or fifth carbons and therefore if you

wrote pip2 people would assume that you

meant for spattered on inositol four or

five bisphosphate rather than maybe

phosphatic diagnosed or free for

bisphosphate okay but if you want to be

strictly correct your suit abbreviated

down to pi/4 five be too okay right so

what I want to do is discuss this

molecule okay so it is a normal

component of the phospholipid bilayer of

the plasma membrane okay it's quite a

rare phospholipid to find in the plasma

membrane okay but it is there is the

important thing so you would have it in

the cell membranes of all of your cells

basically okay so that's discuss the

structure for spattered on inositol 45

bisphosphate now we're not going to draw

out an actual a chemical formula for it

what we're going to do is draw out a

cartoon for what it looks like so that

we can understand what phosphoinositide

3-kinase type 1 enzymes are going to do

to it okay right so let's draw the

plasma membrane here okay and this

flying here is going to represent the

outer leaflet of the plasma

membrane and this line here is going to

represent the inner leaflet of the

plasma membrane okay now phosphors down

and I was still 45 bisphosphate is going

to be a component it's going to be a

phospholipid within the inner leaflet of

the phospholipid bilayer so let me share

it here okay so we'll start off we'll go

for its name in parts okay so we'll

start off with the phosphated I'll let's

try and understand what this phosphate

at our prefix that we have in the name

means here okay so what this means is

that the molecule is based on another

molecule called phosphate it occurred

okay so phosphated on inositol 45

bisphosphate is going to contain

phosphor tiba Cassatt okay so what's the

structure of phosphatic acid so the

specific acid is based on glycerol okay

glycerol is the backbone for phosphor

tillich acid so this horizontal line

that I've now colored in green this is

going to represent a glycerol molecule a

free carbon molecule with alcohol groups

coming off each of the three carbons

okay so remember the more correct name

now for glycerol is propane 1 2 3 trial

glycerol is the old biochemist name for

this molecule the new chemistry name is

propane 12 free trial which tells us

that it is a free carbon molecule

propane we've got alcohol groups coming

off the first second and third carbons

okay right then what you have done is

attached onto the alcohol grouping of

the first and the alcohol grouping of

the second carbons you've attached on

long chain carboxylic acids which are

these vertical lines in orange here okay

so these are representing fatty acids

now fatty acid is just a carboxylic acid

which has a really long hydrophobic tail

okay so these are the lipid molecules

that you have got in this molecule

basically and these are what are holding

its attached to the phospholipid bilayer

Oh game so long chain carboxylic acid

and they've been esterified on to the

alcohol groups of the first and second

carbons of the glycerol molecule okay

right then the final thing that makes

phosphor to the castle is that you can

have a phosphate group which is this

purple blob here which is attached onto

the alcohol group comes off the third

carbon of the glycerol molecule okay so

this is a phosphate group and that now

is the complete phosphor to the castle

molecule and hopefully you'll agree that

this is an example of a phospholipid

okay because the characteristics that

you need in order to be a phospholipid

molecule you need to have a phosphate

group that's one of the characteristics

and the other characteristics you need

are lipid admitted component again we've

got to lipid components here these too

long in carboxylic acids has stara fired

on to the alcohol groups of the first

and second carbons of the glycerol

molecule those are our lipid components

okay so photogenic acid itself is a

molecule so this is my cartoon so as a

phospholipid molecule so this is my

cartoon of a phosphoric acid here

sitting in the plasma membrane now we

want to convert phosphatic acid into

phosphated I'll inositol 45 phosphate so

the first thing we'll do is convert it

into phosphated I'll inositol okay so to

convert foster teaneck acid into

phosphate a dial a notice or what you

need to do is attach onto this phosphate

group here and inositol ring ok nan

inositol ring is a six carbon ring ok

where you have alcohol groups coming off

all of the six carbons so the correct

name for no sottile is cyclohexane

123456 hexyl so 1 2 3 4 5 6 and then hex

all

okay right so basically it's a

six-membered carbon ring where the bonds

between the six carbons are single bonds

and you've got alcohol groups coming off

the first the second third fourth and

the fifth and the sixth carbons every

carbon has a single alcohol group coming

off and then to make up the final bonds

a single hydrogen coming off okay now

you're going to attach the alkyl group

of this carbon here which is the first

carbon to the phosphate group here by

our a phosphodiester link again that's

how we've attached the inositol molecule

onto the phosphoric acid molecule this

molecule that was now created here is

what's called phosphate to dial in a

suit on okay now if we want to turn it

into phosphor to dial in those two till

four five bits phosphate we have to

stick to more phosphate groups off the

inositol ring specifically we need to

put them off the four carbons our core

group and the fifth carbons alcohol

group okay so this is the first carbon

here now we'll just count around two

three four five so we want them coming

off the list alcohol group here and off

this can alcohol group here so we're

attaching these phosphate groups via

phosphorus the links to the alcohol

groups that come off the fourth and the

fifth carbons of that in a little room

to create aa spattered I'll inositol 45

bisphosphate pip2 okay right now you

might be asking well why is that not

cool for sat down and those still free

for this phosphate why is that not the

third carbon than that not the fourth

carbon what is the difference between

this carbon here in this carbon here

well the answer is on my picture

absolutely nothing but in reality and

basically it's a subtle reason there is

a subtle difference between the third

carbon and the fifth carbon of the

inositol room now why is there a subtle

difference basically it has to do with

the optical isomerism of the molecule

okay so if you think about cyclohexane

123456 hexyl you will realize that that

molecule is going to have multiple

optical isomers now there are actually

nine different optical isomers of a

nervous at all

okay there's only one thankfully that's

actually used in biology okay that's

called myo-inositol and basically the

third carbon of myo-inositol which is

this one here in this phosphated I'll

inositol molecule okay is subtly

different from the fifth carbon of

myo-inositol okay so these two are not

actually equivalent basically and the

phosphate group in phos fast I'll

inositol 45 bisphosphate does come off

the fifth carbon rather than the third

carbon of the mire inositol okay so just

know that there is a very subtle reason

for why it's called for spattered on

inositol 45 bisphosphate rather than for

spatter down and no store free for this

phosphate and that there is a difference

between hospital and I still free for

biz phosphate and for staffers are no

store 45 bisphosphate even though it is

such a one certainly can't be shown

online crude little picture here okay

right so that's a the phosphate italiano

still 45 bisphosphate molecule as I say

it's a normal component of the

phospholipid by there is a phospholipid

okay it's not the most common phosphor

they defined in the plasma membrane but

it is present in a small amount okay

right so type warm phosphoinositide

3-kinase is then they are going to

phosphorylate phosphated I'll inositol

45 bisphosphate molecules that are in

the plasma membrane on the third carbon

of inositol ring okay so they're going

to add a phosphate group onto the

alcohol group that comes off this third

carbon of the inositol room here in

false pass down a note or four or five

bisphosphate and therefore what they're

going to turn this into is if i draw an

hour all the product so once again

that's just draw out quickly the

phosphor titik acid structure here okay

so here just as a revision here are the

long-chain carboxylic acids here is the

glycerol molecule here is the phosphate

groups that's the phosphor typical said

then we're going to have the inositol

ring here to create phosphated I'll

inositol and

then what we're going to now have is

phosphate groups coming off the alcohol

group so the third the fourth and little

bit fifth carbons okay like so so one

here one here and one here like so and

then we'll color them in so this is what

type warm phosphoinositide 3-kinase

enzymes are going to do two phosphate

are down and also tore 45 bisphosphate

they're going to convert it into this

molecule here so what is this molecule

cord will for sure it's just called pip3

for phosphated Island of Sodor and then

you've got three phosphate groups coming

off the phosphate start a toast or to be

slightly more correcting your

abbreviation you would abbreviate it

down to pi/4 fast as I love those two

three four five and then be free to tell

people where the phosphate groups are

coming off but again just like the fact

that you can get away with abbreviating

pi/4 5 p-2 down to pib to you can get

away with abbreviation p i 3 4 5 p-3

down to pip3 forgive its full name is of

course for span to dial inositol okay

the pie and now we've got free phosphate

groups coming off the inositol ring of

the phosphates down and I store so it's

false fatter than those two three four

five and then Tris phosphate okay or

pip3 just four short right so that is

what type 1 phosphoinositide 3-kinase

enzymes do they convert hospital in

those 245 bisphosphate into frost favor

dile inositol 345 Tris phosphate now

this one you usually do not have any

phosphatic on those two three four five

trisphosphate in the plasma membrane

this is a lot a normal component of the

phosphor they bit buying there okay when

this appears it has a signaling role

basically and the reason that you don't

usually have any phosphate are those two

three four five Tris phosphate in the

plasma membrane is that there is an

enzyme in the well underneath the plasma

membrane whose job it is to return

spattered on inositol 345 twist

phosphate back into phosphated alano

still 45 bisphosphate so as an enzyme

that is active all the time and which

converts pip3 back into pip2 and this

enzyme is known as p10 and that stands

for phosphatase and tensin homologue ok

so the ps4 phosphatase the t is for and

tensin homologue okay and basically this

is an enzyme which sits underneath the

plasma membrane and which will go around

and cleave off that phosphate group

awfully alcohol group of the third

carbonyl phenyl ring and return the

phosphate stylianou total three four

five to its phosphate back down to

phosphated anilos till four or five

bisphosphate so this enzyme I'll stress

it again is always active and it's

always on the lookout for any of these

molecules in the plasma membrane and if

it finds any of them it will destroy

them basically it will return them back

down so this other one and that's why

usually you do not have any PID free

molecules in the plasma membrane it's

not a normal component of the

phospholipid by there okay right so it

only appears transiently basically when

you activate phosphoinositide 3-kinase

a--'s of the first type okay i'm going

to probably end up dropping the type 1

phosphor those type free time users if I

from now on say phosphoinositide

3-kinase I noon type on phosphoinositide

3-kinase we're not going to discuss type

2 or type free at all in this video not

much is known about them and they don't

do the same thing basically they do not

convert pib 2 into pi be free they

phosphorylate other phosphoinositides

basically okay right so what we now want

to see and why was on the point of

telling you about how it's a transient

signal okay so when you activate

phosphor those type 3 kinase is then

they are going to start converting pip2

into pip3 and you're going

is transient appearance of PRP free in

the plasma membrane and it causes

signaling events basically act thanks

downstream proteins as we'll see later

on okay right and that's how pi3 kinase

achieve its signaling function okay

right so now what we want to do is

discuss the structure of

phosphoinositide 3-kinase enzymes we

also want to discuss how many different

types of type 1 phosphoinositide

3-kinase enzymes there are okay so I've

said that there are these three

different types of phosphoinositide

3-kinase enzymes type 1 type 2 type 3

but under the subheading of type 1

phosphoinositide 3-kinase is there are

loads of different types of type 1

phosphoinositide 3-kinase is okay so all

of the enzyme which we're about to look

at our type 1 phosphorus a free

kindnesses they do this they convert PID

to into pip3 but there are more support

than basically there's not just one type

on force for those type 3 kinase I'm

afraid ok so that's what we're going to

now look into so all type 1

phosphoinositide 3-kinase enzymes that

might just put this here so all type 1

pi3 kinase enzymes are hetero diners

basically okay and they are composed of

two separate subunits okay I'll draw

this like so okay so there are two

separate subunits here that make up the

type 14 spinosa tie free time is now one

of these subunits is what's known as the

catalytic subunit of the type 1

phosphoinositide 3-kinase again this is

the one is actually capable of

converting at pip2 into PRP free okay so

it contains the catalytic domain which

has the active site which can convert

pip2 into pip3 the major reaction

okay the other subunits of the

phosphoinositide 3-kinase type one here

which are coloring in turquoise yet this

is what's known as the regulatory

subunit of a type one phosphoinositide

3-kinase and its role is to regulate the

function of the catalytic subunit so

often it ends up inhibiting the

catalytic subunit and stops it from

having effect okay and then only when

you get conformational changes in the

regulatory subunit can then the

catalytic subunit become active and

phosphorylate pip2 into pip3 and okay

right so what we don't want to discuss

is how many different types of catalytic

subunits other for type 1 pi3 kinase it

oh is it turns out that there are four

different catalytic subunits of type 1

pi3 kinase okay and all of these

proteins are a hundred and ten killer

Dalton's in size okay and therefore they

are called PR hundred and ten proteins

ok so the catalytic subunits a type one

pi3 kinase often instead of calling them

the catalytic subunits people will just

call them p 110 because they are a

protein of a hundred and fifty the

Daltons okay right so there are four

different p 110 proteins them and these

are called p 110 alpha p 110 beta PR

hundred and ten gamma and pia hundred

and ten Delta okay so if you want to be

order type 1 pi3 kinase you have four

choices of catalytic subunits to use

here okay now let me tell you about the

jeans the code for these okay because

the nomenclature of the jeans is

slightly confusing ok so the gene for PR

hundred 10 alpha is called pik ok so for

phosphoinositide kinase and then for

some reason that's beyond me they put

the free after the k and i find that

incredibly

using ok so the jeans you do not call

them pi3k you call them a pik free and

then because it's the catalytic subunit

you put see there and then because it's

the catalytic subunit alpha you put an a

there so the gene for P 110 alpha

protein is called pik3ca now the first

time I saw that I just fought someone

amazed typo Oh game as it was meant to

be pi3k CA okay but it's not it is

correctly called pik3ca okay so that's

the June the codes for PR hundred ten

alpha proteins again the P unguent n

beter and Delta and gamma also have

genes that are named in a similar way ok

so the beta gene is called pik free

catalytic subunit and then of course you

put a bee okay so that's its gene

fucking gamma its pik free again and

then catalytic subunits and then it's g4

gana ok and then finally the gene for PR

hundred ten delta is called pik

phosphoinositide kinase free catalytic

subunit and of course d here ok so

that's the naming of cocoons the

proteins are called p110 Alpha Beta

Gamma Delta the G is a called pik free c

and an ABG or d ok right so that's the

one culture for these catalytic subunit

proteins and their associated genes and

actually code for them ok now the next

bit of nomenclature that I want to

introduce you to is that the entire type

1 pi3 kinase heterodimer and I should

have put that word somewhere this is a

heterodimer hetero means different Dinah

means to membered subunit I want to

members structure ok so because the two

structures that make it up are different

as a heterodimer ok now the entire type

1 pi3 kinase heterodimer is named after

which can

oolitic something that you have here

okay so when you are making a type-1 pi3

kinase we've discussed that there are

four options available for which

catalytic subunit you want to use we

haven't talked about the regulatory

something that's going to make it even

more complicated we're going to come to

that okay basically the type 1 pi3

kinase that you then make is named after

which catalytic subunit you chose to put

in there okay so if you make a type 1

pi3 kinase where you have used the P 110

alpha catalytic subunit then your pi3

kinase is going to be called a pi3

kinase alpha okay so you call it the

pi3-kinase alpha if you use the p110

puter it will be called pi3 kinase beta

if you use P a hundred tank gamma pi

3-kinase gamma and then of course p a

hundred ten Delta you would call your pi

3-kinase pi3k knees Delta okay right so

that's a bit of Norman crusher there the

next thing I need to say is that type 1

pi3 kinase is are split up into two

further classes okay so there are the

type 1a pi3 kinase this and the rather

type 1 bbif retirement is ok now the

type 1a pi3 kinase is our pi3 kinase

alpha beta and Delta okay these are the

ones which can be activated by receptor

tyrosine kinases okay the type 1b pi3

kinase is then pi3 kinase dama and this

is the one which cannot be activated by

receptor tyrosine kinase is as we'll

discuss okay so remember this naming

here just refers to which catalytic

something that you have used so if you

use peer hunt and alpha piano 10 p-2 a

piano in 10 Delta you end up with a pi3

kinase Alphabeat or Delta and that's

called a type on a pi3 kinase okay the

if you use p-element angana you end the

word

time is down and that's called a type 1

B pi3 kinase and what's key here is that

the difference between them is firstly

that they're going to be activated by

different things ok so the receptor

tyrosine kinase is going to be able to

activate the type 1 a's but not the type

1b is another reason that receptor

tyrosine kinases can activate these ones

and not these ones is that the type 1a

is all have certain types of regulatory

subunits so all of these types of pi3

kinase where you've used PR hundred ten

alpha beta and Delta as your catalytic

subunit they're going to have a certain

type of regulatory subunit that could be

used and attached to them whereas pi3

kinase gamma where you have used PR

engine 10 cameras your catalytic

subunits that's going to have totally

different regulatory subunits that can

be attached to it okay and we'll have a

look at the regulatory subunits in the

next video

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