Ras-Raf-MEK-ERK pathway

Chang F, Steelman LS, Lee JT, Shelton JG, et al. 2003. Signal transduction mediated by the Ras/Raf/MEK/ERK pathway from cytokines to transcription factors potential targeting for therapeutic intervention. Leukemia. 17 1263-1293. 

Fig. 10.3 S ummary of the three major MAPK pathways in mammals. In addition to the Ras/Raf/ MEK/ERK pathway, which are activated by receptor tyrosine kinases, there are two major MAPK pathways, the SAPK/JNK pathway and the p38 pathway, which are activated by other signals, e. g., UV irradiation, heat stress and cell-cell interactions. How these other signals are registered and passed to the small regulatory CTPases or to downstrem protein kinases is only incompletely known. Protein kinases...

Wong K-K (2009) Recent developments in anti-cancer agents targeting the Ras/Raf/ MEK/ERK pathway. Recent Pat Anti-Cancer Drug Discovery 4(8) 28-35. doi 10.2174/ 157489209787002461... 

Phosphorylation of H3 is not limited to mitosis and also occurs in G1 phase of the cell cycle. Activation of the Ras-Raf-MEK-ERK signal transduction pathway and/or of the p38 stress kinase pathway when cells are treated with epidermal growth factor (EGF), 12-G-tetradecanoylphorbol-13-acetate (TPA), anesomycin, okadiac acid, and stresses such as UV irradiation induces the rapid phosphorylation of H3 at Ser-10 and/or Ser-28 [68-72] (Figs. 5 and 6). Inhibition of the MEK1,2 activity with PD98059 prevents the activation of ERK and TPA-induced H3... 

Stimulation of ovarian granulosa cells with follicle-stimulating hormone results in the phosphorylation of H3 at Ser-10 [74]. However, neither the Ras-Raf-MEK-ERK signal transduction nor the p38 stress kinase pathways are involved in this response. 

There are at least three major effector pathways that are activated by neurotrophic factor-Trk receptors. The best-characterized pathway is the extracellular-regulated kinase (ERK) cascade, which is regifiated by activation of Ras, a small membrane-bound G protein. Activation of Ras occurs when activated Trk receptor associates with adaptor proteins and a GTP exchange factor (see Russell and Duman 2002 for details). Ras in turn recruits and activates a serine threonine kinase, Raf, to the membrane resulting in the activation of ERK kinase (also referred to as MEK) and ERK (also known as mitogen activated protein kinase or MAPK). Activation of the Ras-Raf-MEK-ERK cascade can lead to regifiation of many celMar proteins, including ribosomal S6-kinase (RSK). 

Dumaz N, Marais R (2005) Integrating signals between cAMP and the RAS/RAF/MEK/ERK signalling pathways. Based on the anniversary prize of the Gesellschaft fur Biochemie und Molekularbiologie Lecture delivered on 5 July 2003 at the Special FEBS Meeting in Brussels. FEBS J 272 3491-3504... 

Manousaridis, 1., Mavridou, S., Goerdt, S., Leverkus, M., Utikal, J. (2013) Cutaneous side effects of inhibitors of the RAS/RAF/ MEK/ERK signalling pathway and their management. J Eur Acad Dermatol Venereal, 27 (1), 11-18. 

CREB is also phosphorylated on serine 133 by stimulation of growth factor signaling cascades [63]. This occurs via a complex pathway involving MAPK cascades (Fig. 23-9). Thus, as outlined earlier, nerve growth factor and related neurotrophins that act on receptor tyrosine kinases lead to the successive activation of Ras, Raf, MEK and ERK. Activated ERK then phosphorylates and activates a serine-threonine kinase, RSK, particular subtypes of which directly activate CREB via the phosphorylation of serine 133. 

Raf activates the ERK mitogen-activated protein kinase cascade (Raf-MEK-ERK), whereas PI3K regulates phospholipid metabolism, and RalGEEs serve as activators of Ras-like (Ral) small GTPases. These and other pro-growth effectors (e.g., phospholipase C epsilon or Tiaml) promote Ras-mediated cellular proliferation and differentiation. In contrast, other Ras effector pathways (most notably Norel and other RASSF family members) can contribute to apoptosis (34). 

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