MAPK/ERK pathway: Difference between revisions
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<StructureSection load='3i2t' size='350' side='right' scene='' caption='Glycosylated EGFR (PDB code [[3i2t]])'> | <StructureSection load='3i2t' size='350' side='right' scene='' caption='Glycosylated EGFR (PDB code [[3i2t]])'> | ||
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. | 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. | ||
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===MAPKs=== | ===MAPKs=== | ||
*[[Mitogen-activated protein kinase kinase]] | *[[Mitogen-activated protein kinase kinase]] '''(MEK1 or MEK2)''' | ||
*[[Mitogen-activated protein kinase]] | *[[Mitogen-activated protein kinase]] | ||
*[[Michael Roberts/BIOL115/ERK2]] | *[[Michael Roberts/BIOL115/ERK2]] | ||
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====MAPK phosphorylates and activates MNK, which, in turn, phosphorylates CREB. The activated CREB protein then binds to a CRE region, and is then bound to by CBP ([[CREB-binding protein]]), which coactivates it, allowing it to switch certain genes on or off. CBP is a transcription activator.==== | ====MAPK phosphorylates and activates MNK, which, in turn, phosphorylates CREB. The activated CREB protein then binds to a CRE region, and is then bound to by CBP ([[CREB-binding protein]]), which coactivates it, allowing it to switch certain genes on or off. CBP is a transcription activator.==== | ||
Genes whose transcription is regulated by CREB include: ''c-fos'', BDNF, [[tyrosine hydroxylase]], numerous [[neuropeptides]] (such as somatostatin, [[enkephalin]], VGF, | Genes whose transcription is regulated by CREB include: ''c-fos'', BDNF, [[tyrosine hydroxylase]], numerous [[neuropeptides]] (such as somatostatin, [[enkephalin]], VGF, corticotropin-releasing hormone), and genes involved in the mammalian [[circadian clock]] ([[PER1]], [[PER2]]). | ||
==Clinical significance== | |||
===Raf kinase inhibitors=== | |||
*The first drug licensed to act on this pathway is [[sorafenib]] — a Raf kinase inhibitor. | |||
*'''Dabrafenib''' ''e.g.'' [[4xv2]] - B-Raf Kinase V600E oncogenic mutant in complex with Dabrafenib. | |||
*B-Raf Kinase Inhibitor Zelboraf - Generic: '''Vemurafenib''' (Formerly: PLX-4032), see [[B-RAF with PLX4032]]. | |||
===MEK inhibitor=== | |||
*'''Cobimetinib''' or XL518, approved by US FDA in Nov 2015 for use in combination with vemurafenib (Zelboraf(R)), for treatment of advanced melanoma with a BRAF V600E or V600K mutation (see above). [[4lmn]] - MEK1 kinase bound to MEK1 kinase bound to Cobimetinib (GDC0973). | |||
</StructureSection> | </StructureSection> | ||
== References == | == References == | ||
<references/> | <references/> | ||