Erk Activation
Growth factors and mitogens use the Ras/Raf/MEK/ERK signaling cascade to transmit signals from their receptors to regulate gene expression and prevent apoptosis.
1. J Immunol. 2010 Jul 15;185 2 :1037-44. doi: 10.4049/jimmunol.0903586. Epub 2010 Jun 16. Glutamine uptake and metabolism are coordinately regulated by ERK/MAPK.
The MAPK Mitogen-Activated Protein Kinase pathway is one of the primordial signaling systems that nature has used in several permutations to accomplish an amazing.
Crosstalk in lymphocyte activation. A more complex, specific example of crosstalk between two major signaling pathways can be observed with the interaction of the.
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.
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1. Oncogene. 2013 Oct 10;32 41 :4873-82. doi: 10.1038/onc.2012.505. Epub 2012 Nov 19. Claudin-1 induces epithelial-mesenchymal transition through activation of the c.
Key components of the MAPK/ERK pathway. P represents phosphate, which communicates the signal. Top, epidermal growth factor EGF binds to the EGF receptor EGFR in the cell membrane, starting the cascade of signals. Further downstream, phosphate signal activates MAPK also known as ERK. Bottom, signal enters the cell nucleus and causes transcription of DNA, which is then expressed as protein.
The MAPK/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, which acts as an on or off switch. Also known as the Ras-Raf-MEK-ERK pathway.
When one of the proteins in the pathway is mutated, it can be 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. 1
Overall, the extracellular mitogen binds to the membrane receptor. This allows Ras a 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.
Coupling cell surface receptors to G proteins edit
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 contains an SH2 domain that binds to the phosphotyrosine residues of the activated receptor. 2 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. 3 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. 4 RAF kinase phosphorylates and activates MEK MEK1 and MEK2. MEK phosphorylates and activates a mitogen-activated protein kinase MAPK.
RAF, and MAPK are both serine/threonine-selective protein kinases. MEK also known as MAPKK is a 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.
Regulation of translation and transcription edit
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.
This section requires expansion. December 2008
Uncontrolled growth is a necessary step for the development of all cancers. 6 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. 7 8 9 10 11 e.g. Hodgkin disease 12
The first drug licensed to act on this pathway is sorafenib a Raf kinase inhibitor.
Other Raf inhibitors : SB590885, PLX4720, XL281, RAF265, LGX818, dabrafenib, vemurafenib. 11
Some MEK inhibitors : XL518, CI-1040, PD035901, MEK162, selumetinib, 11 Trametinib GSK1120212 13
See also Mitogen-activated protein kinase MAP kinases as therapeutic targets
Protein microarray analysis can be used to detect subtle changes in protein activity in signaling pathways. 14
The developmental syndromes caused by germline mutations in genes that alter the RAS components of the MAP/ERK signal transduction pathway are called RASopathies.
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