Ras
REOVIRUS (Respiratory Enteric Orphan Virus)
CAAX
X = Met, Ser, Cys
X = Leu, Ile
FTasiZn
Zn
GGTasi I
CXCXC
GGTasi II
Rab
Zarnestra (Tipifarnib, R115777) Sarasar (Lonafarnib, SCH66336)
EVIDENZE A FAVORE DI UN EFFETTO Ras-INDIPENDENTE PER GLI FTI
• mancanza di correlazione tra suscettibilità e status di Ras
• discrepanze nella cinetica con cui si sviluppano gli effetti • inibizione di della crescita cellulare dipendente da K-Ras e N-Ras
MAPK pathways
MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; ERK, extracellular signal-regulated kinase
Stimulus
MAPKKKMAPKKK
MAPKKMAPKK
MAPKMAPK
Biologicresponse
AMLKs, TAK,ASK1
AMLKs, TAK,ASK1
MKK3/6MKK3/6
P38 MAPK/
P38 MAPK/
MEKK1,4MLKsASK1
MEKK1,4MLKsASK1
MKK4/7MKK4/7
SAPK/JNK1,2,3SAPK/
JNK1,2,3
Inflammation, apoptosis,proliferation, differentiation
Stress, inflammatory cytokines,growth factors
Proliferation, differentiation,
development, survival
A-Raf, B-Raf,C-Raf
A-Raf, B-Raf,C-Raf
Growth factors,mitogens
ERK1/2ERK1/2
MEK1/2MEK1/2
MAPK pathways
AMLKs, TAK,ASK1
MKK3/6
P38 MAPK/
MEKK1,4MLKsASK1
MKK4/7
SAPK/JNK1,2,3
Inflammation, apoptosis,growth, differentiation
Stress, inflammatory cytokines,growth factors
Stimulus
MAPKKKMAPKKKMAPKKKMAPKKK
MAPKKMAPKKMAPKKMAPKK
MAPKMAPKMAPKMAPK
Biologicresponse
A-Raf, B-Raf,C-Raf
A-Raf, B-Raf,C-Raf
Growth factors,mitogens
ERK1/2ERK1/2
MEK1/2MEK1/2
Proliferation, differentiation,
development, survivalMAPK, mitogen-activated protein kinase; MEK, MAPK kinase; ERK, extracellular signal-regulated kinase
The role of MEK1/2
SHCGrb2
SOS1
PP
P
Raf1Raf1P
MEK2P
MEK1P
Grb2, growth factor receptor-bound protein 2
RasRas
ERK2ERK2
ERK1ERK1
The role of MEK1/2
SHCGrb2
SOS1
PP
P
Raf1Raf1P
MEK2P
ERK2ERK2P
P
ERK1ERK1 PP
MEK1P
Transcription factorsTranscription factorsGrb2, growth factor receptor-bound protein 2; SRF, serum response factor
RasRas
SRF SRFTranscriptionTranscription
Constitutive Ras-Raf-MEK-ERK activation
Raf1Raf1P
MEK2P
ERK2ERK2P
P
ERK1ERK1 PP
MEK1P
SRF SRF
RasRas
TranscriptionTranscription
MEK1/2 inhibition
SHCGrb2
SOS1
PP
P
Raf1Raf1P
MEK2P
MEK1P
RasRas
MEK1/2 inhibitionMEK1/2 inhibition
ERK2
ERK1