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