RAF/MAP kinase cascade

Stable Identifier
R-HSA-5673001
Type
Pathway
Species
Homo sapiens
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The RAS-RAF-MEK-ERK pathway regulates processes such as proliferation, differentiation, survival, senescence and cell motility in response to growth factors, hormones and cytokines, among others. Binding of these stimuli to receptors in the plasma membrane promotes the GEF-mediated activation of RAS at the plasma membrane and initiates the three-tiered kinase cascade of the conventional MAPK cascades. GTP-bound RAS recruits RAF (the MAPK kinase kinase), and promotes its dimerization and activation (reviewed in Cseh et al, 2014; Roskoski, 2010; McKay and Morrison, 2007; Wellbrock et al, 2004). Activated RAF phosphorylates the MAPK kinase proteins MEK1 and MEK2 (also known as MAP2K1 and MAP2K2), which in turn phophorylate the proline-directed kinases ERK1 and 2 (also known as MAPK3 and MAPK1) (reviewed in Roskoski, 2012a, b; Kryiakis and Avruch, 2012). Activated ERK proteins may undergo dimerization and have identified targets in both the nucleus and the cytosol; consistent with this, a proportion of activated ERK protein relocalizes to the nucleus in response to stimuli (reviewed in Roskoski 2012b; Turjanski et al, 2007; Plotnikov et al, 2010; Cargnello et al, 2011). Although initially seen as a linear cascade originating at the plasma membrane and culminating in the nucleus, the RAS/RAF MAPK cascade is now also known to be activated from various intracellular location. Temporal and spatial specificity of the cascade is achieved in part through the interaction of pathway components with numerous scaffolding proteins (reviewed in McKay and Morrison, 2007; Brown and Sacks, 2009).
The importance of the RAS/RAF MAPK cascade is highlighted by the fact that components of this pathway are mutated with high frequency in a large number of human cancers. Activating mutations in RAS are found in approximately one third of human cancers, while ~8% of tumors express an activated form of BRAF (Roberts and Der, 2007; Davies et al, 2002; Cantwell-Dorris et al, 2011).

Literature References
PubMed ID Title Journal Year
19091303 Protein scaffolds in MAP kinase signalling

Brown, MD, Sacks, DB

Cell. Signal. 2009
22177953 MEK1/2 dual-specificity protein kinases: structure and regulation

Roskoski, R Jr

Biochem. Biophys. Res. Commun. 2012
21388974 BRAFV600E: implications for carcinogenesis and molecular therapy

Cantwell-Dorris, ER, O'Leary, JJ, Sheils, OM

Mol. Cancer Ther. 2011
12068308 Mutations of the BRAF gene in human cancer

Davies, H, Bignell, GR, Cox, C, Stephens, P, Edkins, S, Clegg, S, Teague, J, Woffendin, H, Garnett, MJ, Bottomley, W, Davis, N, Dicks, E, Ewing, R, Floyd, Y, Gray, K, Hall, S, Hawes, R, Hughes, J, Kosmidou, V, Menzies, A, Mould, C, Parker, A, Stevens, C, Watt, S, Hooper, S, Wilson, R, Jayatilake, H, Gusterson, BA, Cooper, C, Shipley, J, Hargrave, D, Pritchard-Jones, K, Maitland, N, Chenevix-Trench, G, Riggins, GJ, Bigner, DD, Palmieri, G, Cossu, A, Flanagan, A, Nicholson, A, Ho, JW, Leung, SY, Yuen, ST, Weber, BL, Seigler, HF, Darrow, TL, Paterson, H, Marais, R, Marshall, CJ, Wooster, R, Stratton, MR, Futreal, PA

Nature 2002
17496919 MAP kinases and the control of nuclear events

Turjanski, AG, VaquƩ, JP, Gutkind, JS

Oncogene 2007
20674547 RAF protein-serine/threonine kinases: structure and regulation

Roskoski, R Jr

Biochem. Biophys. Res. Commun. 2010
15520807 The RAF proteins take centre stage

Wellbrock, C, Karasarides, M, Marais, R

Nat Rev Mol Cell Biol 2004
22535895 Mammalian MAPK signal transduction pathways activated by stress and inflammation: a 10-year update

Kyriakis, JM, Avruch, J

Physiol. Rev. 2012
24937142 "RAF" neighborhood: protein-protein interaction in the Raf/Mek/Erk pathway

Cseh, B, Doma, E, Baccarini, M

FEBS Lett. 2014
17496923 Targeting the Raf-MEK-ERK mitogen-activated protein kinase cascade for the treatment of cancer

Roberts, PJ, Der, CJ

Oncogene 2007
17496910 Integrating signals from RTKs to ERK/MAPK

McKay, MM, Morrison, DK

Oncogene 2007
21167873 The MAPK cascades: signaling components, nuclear roles and mechanisms of nuclear translocation

Plotnikov, A, Zehorai, E, Procaccia, S, Seger, R

Biochim. Biophys. Acta 2011
22569528 ERK1/2 MAP kinases: structure, function, and regulation

Roskoski, R Jr

Pharmacol. Res. 2012
21372320 Activation and function of the MAPKs and their substrates, the MAPK-activated protein kinases

Cargnello, M, Roux, PP

Microbiol. Mol. Biol. Rev. 2011
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