RAS/RAF/MEK/ERK pathway. Upon binding to a ligand, a receptor tyrosine kinase (RTK), a family of receptors that include epidermal growth factor receptor (EGFR) and platelet derived growth factor (PDGF) among others, dimerizes and transphosphorylates an intracellular RTK N-terminal domain. This recruits growth factor receptor-bound protein Grb2, which then binds the guanine exchange factor (GEF) son of sevenless homologue (SOS) at an Src homology 3 (SH3) domain. A small guanosine-nucleotide-binding protein (G-protein), called RAS, translocates to the plasma membrane and is activated by replacing adenosine diphosphate (ADP) with adenosine triphosphate (ATP) by SOS. Activated RAS recruits RAF to the plasma membrane and activates RAF by phosphorylation. RAF phosphorylates the mitogen-activated protein kinase kinase (MAPKK), MEK, which then phosphorylates the downstream kinase, extracellular signal-regulated kinase (ERK) (Chappell et al., 2011). Phosphorylated ERK phosphorylates and activates substrates such as 90-kDa Ribosomal S6 Protein Kinase (RSK) and several transcription factors, such as c-FOS, c-MYC and Elk. Many of these transcription factors are involved in survival, growth or proliferation of the cell.
Oncogenic events in the MAPK pathway. Blue arrows indicate oncogenic events; V600E mutation in BRAF can increase MEK and ERK stimulation, which can result in the development of cancer. notice how the cancer drug, vemurafenib, have opposing roles. While it inhibits BRAF, it can result in MEK and ERK being stimulated through other pathways.
Production of reactive oxygen species. Assembled NADPH oxidase (purple box) transfers electrons (e–) to the phagosomal lumen in the production of reactive oxygen species (shown in red). Green arrows are neutralizing reactions. SOD, superoxide dismutase; MPO, myeloperoxidase.