Ras/Raf/MEK/ERK Flashcards
RasGTP can activate:
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
All ras proteins are___________ on their __________________
This is required for:
Prenylated/farnesylated
CAAX tail
Oncogenic transformation of Ras
What does the lipid on the CAAX tail of ras do?
Attaches ras to the inside of the PM
Ras becomes________________, the tail is ___________ and matured by __________ before _________ on ____________________ leading to_________
Embedded in the ER Proteolysed Methylation Palmitoylation Hras, Nras and Kras4a Association with the membrane
How is the association of Kras4b different from that of the other isoforms?
It is not always palmitoylated but can associate the the membrane via lysine rich region
Mutations in K-ras4B are most prevalent in
Pancreatic tumours
Rare in melanomas
Most therapeutics acting at the level of ras are targeted at
The prenylation stage Ie prenyltransferase
What were the first anti-cancer drugs aimed at ras?
FTIs eg. Tipifarnib
Newly synthesised ras precursors are normally modified by
FT ot GGT-1
Describe Tipifarnib
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
FTIs allow for_______of K-ras4B, allowing it to ___________- need to use FTIs in combination with____ which has severe side effects
Geranylgeranylation
Localise correctly
GGTI
FTIs result in:
LOF of Hras
Prevention of RhoB-F formation
Accumulation of RhoB-GG
Constitutive activation of Ras can result from
Point mutations or unregulated upstream signalling eg. from erbB2
GAPs
Speed up inactivation of ras
eg. p120Ras GAP (isoform)
GEFs
Switch ras on by exchanging GDP for GTP
GDIs
inhibit ras activation and stop downstream signalling
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______
GEFs
GAPs
SH2 domain
How does the activation of SHP2 prevent the activity of RasGAP?
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
The switch I and II regions of ras bind to
downstream signalling molecules
Treating PC12 cells with nerve growth factor induces__________ activation of ERK, leading to __________ into _______
Strong and sustained
Differentiation
Sympathetic-like neurons
Nuclear localisation of active ERK required for __________, cytoplasmic for _______ (mis-localisation __________________)
Proliferation
stem cell localisation
in stem cells promotes carcinoma formation
ERK is a_________ signalling molecule
Two faced
What happens to activated ERK?
It is released from the KSR1 scaffold and recruits downstream kinases and activates them via phosphorylation
What domain of ERK recruits transcription factors for activation?
DEF docking domain
This is essential for induction of immediate early genes and cell cycle progression
