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Cell Signalling > Ras/Raf/MEK/ERK > Flashcards

Ras/Raf/MEK/ERK Flashcards

1
Q

RasGTP can activate:

A

RAF,MEK, ERK leading to transcription changes

PI3K leading to activation of Akt and mTOR, cell survival and proliferation

GEFs: can switch on other G proteins, can activate Rac which activates kinases leading to changes in transcription and cell shape

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2
Q

All ras proteins are___________ on their __________________

This is required for:

A

Prenylated/farnesylated
CAAX tail
Oncogenic transformation of Ras

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3
Q

What does the lipid on the CAAX tail of ras do?

A

Attaches ras to the inside of the PM

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4
Q

Ras becomes________________, the tail is ___________ and matured by __________ before _________ on ____________________ leading to_________

A 
Embedded in the ER
Proteolysed 
Methylation 
Palmitoylation 
Hras, Nras and Kras4a
Association with the membrane
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5
Q

How is the association of Kras4b different from that of the other isoforms?

A

It is not always palmitoylated but can associate the the membrane via lysine rich region

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6
Q

Mutations in K-ras4B are most prevalent in

A

Pancreatic tumours

Rare in melanomas

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7
Q

Most therapeutics acting at the level of ras are targeted at

A

The prenylation stage Ie prenyltransferase

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8
Q

What were the first anti-cancer drugs aimed at ras?

A

FTIs eg. Tipifarnib

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9
Q

Newly synthesised ras precursors are normally modified by

A

FT ot GGT-1

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10
Q

Describe Tipifarnib

A

Tipifarnib has limited success due to lack of specificity causing side effects (due to effects on other proteins with CAAX motif, eg. Rho) but can be used to treat AML. Poor at treating breast cancer on its own- works best as a combination therapy

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11
Q

FTIs allow for_______of K-ras4B, allowing it to ___________- need to use FTIs in combination with____ which has severe side effects

A

Geranylgeranylation
Localise correctly
GGTI

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12
Q

FTIs result in:

A

LOF of Hras
Prevention of RhoB-F formation
Accumulation of RhoB-GG

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13
Q

Constitutive activation of Ras can result from

A

Point mutations or unregulated upstream signalling eg. from erbB2

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14
Q

GAPs

A

Speed up inactivation of ras

eg. p120Ras GAP (isoform)

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15
Q

GEFs

A

Switch ras on by exchanging GDP for GTP

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16
Q

GDIs

A

inhibit ras activation and stop downstream signalling

17
Q

Ras is active when bound to GTP- switch on tyrosine kinase, recruit ____ to switch Ras on, switch off at the same time by recruiting ____ to the same receptor but a different P-Tyr via GAP’s______

A

GEFs
GAPs
SH2 domain

18
Q

How does the activation of SHP2 prevent the activity of RasGAP?

A

SHP2 is recruited to the activated RTK via its SH2 domains where it dephosphorylates the docking site for RasGAP, preventing its recruitment to the membrane via competitive binding. SHP2 undergoes a conformational change when P-Tyr on the receptor becomes available: SH2 domains interact with P-Tyr, exposing the active site which is involved in dephosphorylating p-Try on the receptor. This prevents RasGAP recruitment and Ras remains active

Lacks specificity for therapeutics

19
Q

The switch I and II regions of ras bind to

A

downstream signalling molecules

20
Q

Treating PC12 cells with nerve growth factor induces__________ activation of ERK, leading to __________ into _______

A

Strong and sustained
Differentiation
Sympathetic-like neurons

21
Q

Nuclear localisation of active ERK required for __________, cytoplasmic for _______ (mis-localisation __________________)

A

Proliferation
stem cell localisation
in stem cells promotes carcinoma formation

22
Q

ERK is a_________ signalling molecule

A

Two faced

23
Q

What happens to activated ERK?

A

It is released from the KSR1 scaffold and recruits downstream kinases and activates them via phosphorylation

24
Q

What domain of ERK recruits transcription factors for activation?

A

DEF docking domain

This is essential for induction of immediate early genes and cell cycle progression

25
Q

ERK can shuttle between the nucleus and cytoplasm but

A

No NES or NLS has been identified - thought to bind MEK or MAP kinase phosphatase 3 which do have NES

26
Q

When does ERK not localise to nucleus?

A

When activated by some GPCRs

27
Q

What is the function of PEA-15? What happens when it is deleted?

A

Binds to ERK without inhibiting it’s activation allowing it to sequester ERK activity in the cytoplasm via its NES

28
Q

What other proteins can restrict ERK activation to the cytoplasm?

A

Calponin and beta-arrestin

29
Q

What type of mutations can lead to constitutive activation of MEK/ERK?

A

No known activating mutations in MEK/ERK
Constitutive activity normally due to uncontrolled activation of upstream signalling or mutations in molecules involved in restricting ERK signalling

30
Q

What does ERK activate and how?

A

P90rsk- activated by phosphorylation by ERK and PDK1

31
Q

Describe the structure of P90rsk

A

2 kinase domains

Consists of 4 distinct isoforms

32
Q

What does P90rsk do and how is it associated with cancer?

A

Actively shuttles into nucleus and phosphorylates transcription factors
Overexpressed in breast and prostate cancer cells

33
Q

Where does ERK phosphorylate P90rsk?

A

Thr365, Ser369, Thr577- activates the C-terminal kinase domain which phosphorylates Ser386 to generate a binding site for PDK1

34
Q

Where does PDK1 phosphorylate P90rsk?

A

Ser277 in the N-terminal kinase domain (consists of 2 lobes with ATP binding cleft between them), resulting in activation

35
Q

Where so inhibitors of NTKD of P90rsk bind?

A

ATP binding pocket

36
Q

What is Sprouty and how is its transcription promoted?

A

Family of 4 proteins that represses the later stages of ERK activation
Promoted by activated ERK

37
Q

How is Sprouty activated and what does it do when active?

A

Activated by tyrosine phosphorylation in response to GF stimulation
Inhibits Grb2/sos function- interacts with Grb2, SOS and SHP2 and interferes with their interactions with other molecues

38
Q

Role of Sprouty in cancer?

A

Suppressed in breast, prostate and ovarian cancers

39
Q

What is the effect of Sprouty overexpression?

A

ERK activation becomes transient and suppresses differentiation of PC12 cells
Overexpression of dominant -ve form leads to sustained activation of ERK and promotes PC12 cell differentiation

Cell Signalling (5 decks)

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