The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The MAPK/ERK pathway (also known as the Ras-Raf-MEK-ERK pathway) is a chain of proteins in the cell that communicates a signal from a receptor on the surface of the cell to the DNA in the nucleus of the cell. The signal starts when a signaling molecule binds to the receptor on the cell surface and ends when the DNA in the nucleus expresses a protein and produces some change in the cell, such as cell division. The pathway includes many proteins, including MAPK (mitogen-activated protein kinases, originally called ERK, extracellular signal-regulated kinases), which communicate by adding phosphate groups to a neighboring protein (phosphorylating it), which acts as an 'on' or 'off' switch. When one of the proteins in the pathway is mutated, it can become stuck in the 'on' or 'off' position, which is a necessary step in the development of many cancers. Components of the MAPK/ERK pathway were discovered when they were found in cancer cells. Drugs that reverse the 'on' or 'off' switch are being investigated as cancer treatments. Overall, the extracellular mitogen binds to the membrane receptor. This allows Ras (a Small GTPase) to swap its GDP for a GTP. It can now activate MAP3K (e.g., Raf), which activates MAP2K, which activates MAPK. MAPK can now activate a transcription factor, such as Myc. In more detail: Receptor-linked tyrosine kinases such as the epidermal growth factor receptor (EGFR) are activated by extracellular ligands, such as epidermal growth factor (EGF). Binding of EGF to the EGFR activates the tyrosine kinase activity of the cytoplasmic domain of the receptor. The EGFR becomes phosphorylated on tyrosine residues. Docking proteins such as GRB2 contain an SH2 domain that binds to the phosphotyrosine residues of the activated receptor. GRB2 binds to the guanine nucleotide exchange factor SOS by way of the two SH3 domains of GRB2. When the GRB2-SOS complex docks to phosphorylated EGFR, SOS becomes activated. Activated SOS then promotes the removal of GDP from a member of the Ras subfamily (most notably H-Ras or K-Ras). Ras can then bind GTP and become active. Apart from EGFR, other cell surface receptors that can activate this pathway via GRB2 include Trk A/B, Fibroblast growth factor receptor (FGFR) and PDGFR. Activated Ras activates the protein kinase activity of RAF kinase. RAF kinase phosphorylates and activates MEK (MEK1 and MEK2). MEK phosphorylates and activates a mitogen-activated protein kinase (MAPK). RAF, and ERK (also known as MAPK) are both serine/threonine-selective protein kinases. MEK is a serine/tyrosine/threonine kinase. In the technical sense, RAF, MEK, and MAPK are all mitogen-activated kinases, as is MNK (see below). MAPK was originally called 'extracellular signal-regulated kinases' (ERKs) and 'microtubule associated protein kinase' (MAPK). One of the first proteins known to be phosphorylated by ERK was a microtubule-associated protein (MAP). As discussed below, many additional targets for phosphorylation by MAPK were later found, and the protein was renamed 'mitogen-activated protein kinase' (MAPK). The series of kinases from RAF to MEK to MAPK is an example of a protein kinase cascade. Such series of kinases provide opportunities for feedback regulation and signal amplification.