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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]])'>
'''Under development!!!'''


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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'''B-Raf''' is related to retroviral oncogenes and participates in cellular signal transduction. B-Raf domains include the kinase domain - residues 444-721 and Ras-binding domain - residues 153-237.  Mutated B-Raf was found in some human cancers<ref>PMID:12460918</ref>.  See more in [[B-RAF with PLX4032]].
'''B-Raf''' is related to retroviral oncogenes and participates in cellular signal transduction. B-Raf domains include the kinase domain - residues 444-721 and Ras-binding domain - residues 153-237.  Mutated B-Raf was found in some human cancers<ref>PMID:12460918</ref>.  See more in [[B-RAF with PLX4032]].


'''c-Raf''' is part of the MAPK pathway. c-Raf domains include the kinase domain - residues 323-618, cysteine-rich domain – residues 136-187 and Ras-binding domain - residues 51-132. Mutations of c-Raf are possible causes of Noonan syndrome<ref>PMID:23737487</ref>.  For details on '''c-Raf''' see [[Molecular Playground/C-Raf]].
'''c-Raf''' is part of the MAPK pathway. c-Raf domains include the kinase domain - residues 323-618, cysteine-rich domain – residues 136-187 and Ras-binding domain - residues 51-132. Mutations of c-Raf are possible causes of Noonan syndrome<ref>PMID:23737487</ref>.  For details on '''c-Raf''' see [[Molecular Playground/C-Raf]].


[[Mitogen-activated protein kinase kinase kinase]]
[[Mitogen-activated protein kinase kinase kinase]]


===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, corticotropin-releasing hormone),[2] and genes involved in the mammalian circadian clock (PER1, PER2).
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]]).


Genes whose transcription is regulated by CREB include: ''[[c-fos]]'', [[BDNF]], [[tyrosine hydroxylase]], numerous [[neuropeptide]]s (such as [[somatostatin]], [[enkephalin]], [[VGF]], [[corticotropin-releasing hormone]]),<ref name="Purves" /> and genes involved in the mammalian [[circadian clock]] ([[PER1]], [[PER2]]).<ref name=":0">{{Cite journal|title = The Mammalian Circadian Timing System: Organization and Coordination of Central and Peripheral Clocks|journal = Annual Review of Physiology|date = 2010|pmid = 20148687|pages = 517–549|volume = 72|issue = 1|doi = 10.1146/annurev-physiol-021909-135821|first1 = Charna|last1 = Dibner|first2 = Ueli|last2 = Schibler|first3 = Urs|last3 = Albrecht|url = http://doc.rero.ch/record/17505/files/alb_mct.pdf}}</ref>
==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 ==
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<references/>

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Alexander Berchansky
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