Diagram showing key components of the MAPK/ERK pathway. In the diagram, "P" represents phosphate. See the article main text for details.

The MAPK/ERK pathway is a signal transduction pathway that couples intracellular responses to the binding of growth factors to cell surface receptors. This pathway is very complex and includes many protein components ^[1]. The basic pathway shown in the figure (to the right) and described below includes the major components of the pathway. In many cell types, activation of this pathway promotes cell division.

[edit] Coupling cell surface receptors to G proteins

Receptor-linked tyrosine kinases such as the epidermal growth factor receptor (EGFR) are activated by extracellular ligands. Binding of epidermal growth factor (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 SH2 domains that bind to the phosphotyrosine residues of the activated receptor ^[2]. GRB2 binds to the guanine nucleotide exchange factor SOS by way of an SH3 domain of GRB2. When the GRB2-SOS complex docks to phosphorylated EGFR, SOS becomes activated ^[3]. Activated SOS promotes the removal of GDP from Ras. Ras can then bind GTP and become active. Other small G proteins can be activated in a similar way, but are not discussed further here.

[edit] Kinase cascade

Activated Ras activates the protein kinase activity of RAF kinase ^[4]. RAF kinase phosphorylates and activates MEK. MEK phosphorylates and activates a mitogen-activated protein kinase (MAPK).

RAF, MEK and MAPK are all serine/threonine-selective protein kinases.

Technically, 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. As discussed below, many additional targets for phosphorylation by MAPK were later found and the protein was re-named "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.

[edit] Regulation of translation and transcription

Three of the many proteins that are phosphorylated by MAPK are shown in the Figure. One effect of MAPK activation is to alter the translation of mRNA to proteins. MAPK phosphorylates 40S ribosomal protein S6 kinase (RSK). This activates RSK which in turn phosphorylates ribosomal protein S6 ^[5]. Mitogen-activated protein kinases that phosphorylate ribosomal protein S6 were the first to be isolated ^[4].

MAPK regulates the activities of several transcription factors. MAPK can phosphorylate C-myc. MAPK phosphorylates and activates MNK which in turn phosphorylates CREB. MAPK also regulates the transcription of the C-Fos gene. By altering the levels and activities of transcription factors, MAPK leads to altered transcription of genes that are important for the cell cycle.

The 22q11, 1q42, and 19p13 genes are associated with schizophrenia, schizoaffective, bipolar and migraines by affecting the ERK pathway.

[edit] Clinical significance

This section requires expansion.

The kinase cascade is relevant to many cancers.^{[6] [7] [8] [9]} eg. Hodgkin disease^[10]

The first drug licensed to act on this pathway is sorafenib - a Raf kinase inhibitor.

Protein microarray analysis can be used to detect subtle changes in protein activity in signaling pathways.^[11]

[edit] See also

• Janus kinase
• Phosphatase
• Adaptor protein
• G protein-coupled receptor

[edit] External links

• Kyoto Encyclopedia of Genes and Genomes - MAPK pathway
• MeSH MAP+Kinase+Signaling+System
• MAPK/ERK in Growth and Differentiation Pathway

[edit] References