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cancer > 7. signalling > Flashcards

7. signalling Flashcards

1
Q

what are rich in potential viral oncogenes?

A

signalling pathways - drivers of cancers in various settings.

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2
Q

what is the receptor at the top of the signalling cascade that results in cyclin D/E expression called? describe the viral version

A

ErbB2

vErbB3 lacks the extracellular part and the intracellular part is constituently active

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3
Q

name the central kinase that performs most of its phosphorylation at the membrane. describe the viral version

A

Akt
viral version has alterations meaning that it is permanently attached to the membrane meaning that it is constitutively active

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4
Q

name two viral oncogenic transcription factors that cannot be switched off?

A

v-fos and c-jun

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5
Q

what is conditioned medium?

A

this is media that has been exposed to cells and it will contain all their secretions

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6
Q

what is the difference between cell grown in non-cancerous conditioned medium and cells grown in cancerous conditioned medium? and what does this show?

A

in non-cancerous conditioned medium cells do not proliferate
in cancerous medium, cells proliferate
>cells have secreted something that triggers other cells to enter S phase.

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7
Q

what growth factor was being released from cancer cells?

A

TGFβ

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8
Q

how are cancer cells that secrete TGFβ

self-sustaining?

A

it can act in an autocrine manner

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9
Q

when an antibody that binds a RTK that recognises GF, how does this affect tumour growth?

A

this stops the volume of tumour increasing

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10
Q

how was EGF signalling first seen?

A

proteins harvest from salivary glands of new born mice shown to enhance development, premature opening of eyes and eruption of teeth
>after 20 years he isolated EGF

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11
Q

describe structure of EGF

A

6kDa
53 amino acids
3 disulphide bridges to help maintain structure

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12
Q

describe the paper that first reported the discovery of EGFR

A

> total cells lysate of cells that respond to EGF
purified with high affinity matrixes that bind specific glycosylated proteins
after lots of fractioning one band was seen on gel - EGFR

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13
Q

what did this EGFR band have the equivalent sequence? and what gave them confidence they had found the humans receptor?

A

oncogene v-ErbB
>the fact that they had identified a cellular homologue of this viral oncogene gave them confidence that they had found the human receptor

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14
Q

what antibody is used in an immunoprecipitation to show that when EGFR is activated by EGF it is phosphorylated?

A

anti-phosphotyrosine

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15
Q

describe EGFR

A

> single TM glycoprotein of 2010 aa

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16
Q

what happens when EGFR is activated on the extracellular side?

A

activation of EGFR causes conformational changes which result in the exposure of a single stranded beta hairpin dimerization arm that promotes the dimerization to another receptor, to form a homodimer

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17
Q

describe the intracellular portion of EGFR

A

tyrosine kinas domain followed by regulatory region bearing tyrosines to phosphorylate

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18
Q

what happens on the intracellular side when EGFR has dimerised?

A

intracellular domains are close enough and in the correct orientation for trans-autophosphorylation to occur

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19
Q

what are phosphor-tyrosines on inside of EGFR able to do?

A

transduce the signal to the rest of the cascade.

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20
Q

what is the next protein in the pathway after EGFR? and describe its structure

A

Grb2

it has three domains that fold independently of one another

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21
Q

what are the three domains of Grb2

A

1 Sh2 domain - this binds phospho-tyrosines

2 SH3 domains - these binds proline sich sequence and propagate signal downstream

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22
Q

describe the SH2 domain

A

it is symmetrical

two alpha helixes with some beta strands across the back

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23
Q

name a flexible interaction motif

A

SH3

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24
Q

what gives SH3 domains specificity and can also change its affinity to a certain peptide?

A

> loop structures coming off the beta barrel

> peptide sequence that SH3 is binding

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25
Q

what does Grb2 bind? and why?

A

Son of Sevenless

there are two proline rich regions in SOS

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26
Q

what is the EGFR receptor in Drosophila called?

A

Sevenless

27
Q

what type of protein is SOS?

A

a Ras-GEF

28
Q

where is SOS located? and what implication does this have?

A

in the cytoplasm
>recruited to the membrane by Grb2
>Ras is a membrane bound protein

29
Q

what two mutants in Drosophila look similar?

A

Sevenless and SOS mutants
>EGFR pathway is used in development of eyes
>each bump normally consist of 7 cells
>in mutants they only have 6 and this results in roughened appearance

30
Q

describe SOS function

A

it is a Ras-guanine nucleotide exchange factor

>causes GDP to dissociate from Ras and for GTP to associate to activate Ras

31
Q

why is Ras found at the membrane?

A

it is farnesylated

32
Q

how is Ras inactivated?

A

by hydrolysing GTP to GDP - this can occur intrinsically or accelerated with a GAP - GTPase activating protein

33
Q

what is the major difference in conformational change when Ras is bound GTP?

A

when Ras is activated the effector loop change conformation (forms a more ordered alpha helical structure) and can interact with and regulate the function of other proteins

34
Q

what is the most mutated oncogene in cancer and what implication does this have?

A

Ras

lots of things can occur downstream of Ras signalling e.g. cell cycle progression and cell motility

35
Q

what are the three kinases downstream of Ras and what type of kinase are they?

A

Raf
Mek
Erk
they are serine threonine kinases that sequentially activate each other

36
Q

how is raf activated?

A

it is recruited to the membrane by ras and this activated Raf through an allosteric mechanism

37
Q

what is used to physically organise the MAP kinase module so that P occurs in the correct order and most efficiently?

A

scaffold proteins

38
Q

what happens once Erk is activated?

A

it translocates into the nucleus

39
Q

what does Erk P?

A

Jun and Fos - activates and stabilise them

40
Q

what are jun and Fos?

A

TF that bind to cyclin D1 promoter to drive proliferation

41
Q

from the stimulation of a cell by EGF to this phosphorylation of Jun and Fos takes less than 5 minutes, how long does it take to for the production of cyclin D?

A

up to 5 hours

42
Q

what is one of the most mutated TS in cancer?

A

PTEN

43
Q

what is present on the inner leaflet of the membrane? and what are they?

A

Phosphoionsitides

>they are two fatty acid chains linked to a glycerol which is attacked to an inositol

44
Q

what does PTEN do?

A

remove phosphates added to position 3 of Phosphoionsitides by PI3kinase so that PH domain can no longer bind membrane (prevents ATK activation)

45
Q

what is the regulatory subunit of PI3kinase? describe it?

A

p85
>it has an SH2 domains
>this recruits PI3Kinase to the membrane so that it can P Phosphoionsitides

46
Q

how is PI3kinas kept unactive in non-stimulated cells?

A

it is not localised to the membrane

47
Q

when localised to the membrane, what does PI3Kinase do??

A

it uses ATP to attach phosphate to the 3 position on the inositol head group of inositol group of Phosphoionsitides
>produces 3 different species that are signalling molecules: PIP, PIP2, PIP3

48
Q

what levels rapidly rise after RTK stimulation with GF? and what does this imply? what levels don’t change?

A

PIP2 and PIP3
>they are important for downstream signalling - they are the second messengers
>PIP levels don’t change

49
Q

what can PIP3 function as?

A

a docking site for other proteins to be activated on the membrane

50
Q

what domain binds PIP3? and what do they bind? describe this interaction

A

PH domains
>they bind phosphorylated inositol head groups
>the loops between two beta strands have a high affinity of binding to PIP3

51
Q

name two proteins that have PH domains, and what happens when they are recruited to the membrane?

A

PDK1 and AKT
>PDK1 is constitutively active, when brought to membrane in close proximity to AKT it P AKT and partially activates it. mTOR P ATK again to fully activate it.

52
Q

ATK P lots of things, give some examples

A

> AKT contributes to cell cycle progression through the phosphorylation of CDK inhibitors p21 and p27
they are excluded from nucleus
p21 is then degraded

53
Q

what P cyclin D and what affect does this have?

A

GSK3

this results in cyclin D degradation

54
Q

what inhibits GSK3 and what affect does this have?

A

P by ATK

>this is an inhibitory phosphorylation which results in the stabilisation on cyclin D1

55
Q

what TF leads to the activation of p27? and how is this regulated by ATK?

A

FOXO

AKT can P this causing its nuclear exclusion

56
Q

what two types of affects does AKT have?

A

pro-proliferative and anti-apoptotic

57
Q

define how ATK has anti-apoptotic affects?

A

inactivated Bax

upregulates Bcl2

58
Q

what are mice heterozygous for PTEN like?

A

they are more prone to tumours in some tissues over others

59
Q

what are the two types of therapeutic intervention made on EGFR and what do they do?

A
  • monocolonal antibody prevent EGF from binding receptor

- small molecule that inhibits EGFR kinase activity

60
Q

why do farnesyltransferase inhibitors inhibit that prevent Ras from being localised to the membrane have no therapeutic value?

A

other enzymes that can add other lipids to Ras in order to localize it to the membrane for it to have activity

61
Q

how is Raf being therapeutically targeted?

A

there is a common mutations found in melanomas in Raf. there is a small molecule that targets this mutant and not the WT form and so does not have off target effect. this has proven clinically useful.

62
Q

how is ATK being targeted therapeutically?

A

> it has proven hard to directly inhibit this

>blocking its recruitment to the membrane prevents activation

63
Q

why is can very specifically targeting something in cancer eventually not work?

A

> cancer cells genomes are very unstable

>applying a selective pressure will select for cells that are resistant to drugs

cancer (24 decks)

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