MAPK/ERK pathway

Cell signaling pathway

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, such as mitogen activated protein kinases (MAPKs), originally called extracellular signal regulated kinases (ERKs), which communicate by adding phosphate groups to a neighboring protein (phosphorylating it), thereby acting 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, a necessary step in the development of many cancers. In fact, components of the MAPK/ERK pathway were first discovered in cancer cells, and drugs that reverse the "on" or "off" switch are being investigated as cancer treatments.

The signal that starts the MAPK/ERK pathway is the binding of extracellular mitogen to a cell surface receptor. This allows a Ras protein (a Small GTPase) to swap a GDP molecule for a GTP molecule, flipping the "on/off switch" of the pathway. The Ras protein can then activate MAP3K (e. g., Raf), which activates MAP2K, which activates MAPK. Finally, MAPK can activate a transcription factor, such as Myc. This process is described in more detail below.

Receptor linked tyrosine kinases, such as the epidermal growth factor receptor (EGFR), are activated by extracellular ligands, such as the 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). The Ras protein 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 then activates the protein kinase activity of a RAF kinase. The RAF kinase phosphorylates and activates a MAPK/ERK Kinase (MEK1 or MEK2). The MEK phosphorylates and activates a mitogen activated protein kinase (MAPK). RAF and MAPK/ERK are both serine/threonine specific protein kinases. MEK is a serine/tyrosine/threonine kinase. In a technical sense, RAF, MEK, and MAPK are all mitogen activated kinases, as is MNK (see below). MAPKs were originally called "extracellular signal regulated kinases" (ERKs) and "microtubule associated protein kinases" (MAPKs). 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.

Uncontrolled growth is a necessary step for the development of all cancers. In many cancers (e. g. melanoma), a defect in the MAP/ERK pathway leads to that uncontrolled growth. Many compounds can inhibit steps in the MAP/ERK pathway, and therefore are potential drugs for treating cancer, such as Hodgkin disease. The first drug licensed to act on this pathway is sorafenib — a Raf kinase inhibitor. Other Raf inhibitors include SB590885, PLX4720, XL281, RAF265, encorafenib, dabrafenib, and vemurafenib. It has been found that acupoint moxibustion has a role in relieving alcohol induced gastric mucosal injury in a mouse model, which may be closely associated with its effects in up regulating activities of the epidermal growth factor/ERK signal transduction pathway. RAF ERK pathway is also involved in the pathophysiology of Noonan syndrome, a polymalformative disease. Protein microarray analysis can be used to detect subtle changes in protein activity in signaling pathways. The developmental syndromes caused by germline mutations in genes that alter the RAS components of the MAP/ERK signal transduction pathway are called RASopathies.