View source for MAPK/ERK pathway

[[Image:MAPKpathway.png|thumb|right|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 factor]]s to [[cell (biology)|cell]] surface [[Receptor (biochemistry)|receptor]]s. This pathway is very complex and includes many [[protein]] components <ref name="Orton2005"> R. J. Orton, O. E. Sturm, V. Vyshemirsky, M. Calder, D. R. Gilbert and W. Kolch (2005) "Computational modelling of the receptor-tyrosine-kinase-activated MAPK pathway" in ''[[Biochemical journal|The Biochemical journal]]'' Volume 392, pages 249-261. Review.{{Entrez Pubmed|16293107}}.</ref>. 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]]. 

==Coupling cell surface receptors to G proteins==
Receptor-linked [[tyrosine kinase]]s such as the [[epidermal growth factor receptor]] (EGFR) are activated by extracellular [[Ligand (biochemistry)|ligand]]s. Binding of epidermal growth factor (EGF) to the EGFR activates the tyrosine kinase activity of the cytoplasmic domain of the receptor. The EGFR becomes [[phosphorylation|phosphorylated]] on tyrosines. Docking proteins such as [[GRB2]] contain [[SH2 domain]]s that bind to the phosphotyrosines of the activated receptor <ref name="Schulze2005"> W. X. Schulze, L. Deng and M. Mann (2005) "Phosphotyrosine interactome of the ErbB-receptor kinase family" in ''Molecular systems biology'' Volume 1, May 25.{{Entrez Pubmed|16729043}}.</ref>. GRB2 binds to the [[Nucleotide exchange factor#Guanine NEFs|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 <ref name="Zarich2006"> N. Zarich, J. L. Oliva, N. Martinez, R. Jorge, A. Ballester, S. Gutierrez-Eisman, S. Garcia-Vargas and J. N. Rojas (2006) "Grb2 Is a Negative Modulator of the Intrinsic Ras-GEF Activity of hSos1" in ''Molecular Biology of the Cell'' Epub ahead of print.{{Entrez Pubmed|16760435}}.</ref>. Activated SOS promotes the removal of [[Guanosine diphosphate|GDP]] from [[Ras]]. Ras can then bind [[Guanosine triphosphate|GTP]] and become active. Other [[Small GTPase|small G proteins]] can be activated in a similar way, but are not discussed further here.

==Kinase cascade==
Activated Ras activates the protein kinase activity of [[C-Raf|RAF]] kinase <ref name="Avruch2001">J. Avruch, A. Khokhlatchev, J. M. Kyriakis, Z. Luo, G. Tzivion, D. Vavvas and X. F. Zhang (2001) "Ras activation of the Raf kinase: tyrosine kinase recruitment of the MAP kinase cascade" in ''Recent Progress in Hormone Research'' Volume 56, pages 127-155. {{Entrez Pubmed|11237210}}.</ref>, a serine/threonine-selective [[protein kinase]]. RAF kinase phosphorylates and activates MEK, another serine/threonine kinase. MEK phosphorylates and activates [[mitogen-activated protein kinase]] (MAPK).

Technically, RAF, MEK and MAPK are all [[mitogen]]-activated kinases, as is MNK (see below). MAPK was originally called "extracellular signal-regulated kinase" (ERK) 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.

==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 (genetics)|translation]] of [[mRNA]] to proteins. MAPK phosphorylates 40S [[ribosome|ribosomal]] protein S6 kinase (RSK). This activates RSK which in turn phosphorylates ribosomal protein S6 <ref name="Pende2004">M. Pende, S. H. Um, V. Mieulet, M. Sticker, V. L. Goss, J. Mestan, M. Mueller, S. Fumagalli, S. C. Kozma and G. Thomas.(2004) "S6K1,<sup>(-/-)</sup>/S6K2<sup>(-/-)</sup> mice exhibit perinatal lethality and rapamycin-sensitive 5'-terminal oligopyrimidine mRNA translation and reveal a mitogen-activated protein kinase-dependent S6 kinase pathway" in ''Molecular and Cellular Biology'' Volume 24, pages 3112-3124. {{Entrez Pubmed|15060135}}.</ref>. Mitogen-activated protein kinases that phosphorylate ribosomal protein S6 were the first to be isolated <ref name="Avruch2001" />.

MAPK regulates the activities of several [[transcription factor]]s. MAPK can phosphorylate [[C-myc]]. MAPK phosphorylates and activates MNK which in turn phosphorylates [[CREB]]. MAPK also regulates the transcription of the [[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]].

==See also==
*[[Janus kinase]]
*[[Phosphatase]]
*[[Adaptor protein]]
*[[G protein-coupled receptor]]

==External links==
*[[KEGG PATHWAY Database|Kyoto Encyclopedia of Genes and Genomes]] - [http://www.genome.ad.jp/dbget-bin/show_pathway?hsa04010+5594 MAPK pathway]
*{{MeshName|MAP+Kinase+Signaling+System}}

==References==
<div class="references-small">{{reflist|2}}</div>

{{Signaling proteins}}
{{Signal transduction}}
[[Category:Signal transduction]]
[[Category:Cell signaling]]
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