MAPK/ERK pathway: Difference between revisions

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Alexander Berchansky

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 <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.
-*Cell surface receptors that can activate this pathway via GRB2:
+==Cell surface receptors that can activate this pathway via GRB2==
 [[Epidermal Growth Factor Receptor]] (EGFR; see also [[Epidermal growth factor]]). EGFR belongs to [[Receptor tyrosine kinases]], class I.
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 [[Platelet-derived growth factors and receptors]]
-*[[Growth factor receptor-bound proteins]] (GRB) are adaptor proteins. GRBs contain SH2, Ras-associated (RA) and pleckstrin homology (PH) domains. For additional details on GRB10 see [[Grb10 SH2 Domain]].
+==[[Growth factor receptor-bound proteins]]==
+Growth factor receptor-bound proteins (GRB) are adaptor proteins. GRBs contain SH2, Ras-associated (RA) and pleckstrin homology (PH) domains. For additional details on GRB10 see [[Grb10 SH2 Domain]].
-*[[Rho guanine nucleotide exchange factor]].
+==[[Rho guanine nucleotide exchange factor]]==
-*Ras subfamily: [[GTPase KRas]] and [[Allosteric modulation of H-Ras GTPase]].
+==Ras activation==
+[[GTPase KRas]]
-*RAF kinase:
+[[Allosteric modulation of H-Ras GTPase]].
-* '''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]].
+==Kinase cascade==
+===RAF kinase===
+'''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]].
+[[Mitogen-activated protein kinase kinase kinase]]
+===MAPKs===
+*[[Mitogen-activated protein kinase kinase]] '''(MEK1 or MEK2)'''
+*[[Mitogen-activated protein kinase]]
+*[[Michael Roberts/BIOL115/ERK2]]
+*[[UMass Chem 423 Student Projects 2011-2#p38 kinase|p38 MAPK (UMass Chem 423 Student Projects 2011-2)]]
+==Targets for phosphorylation by MAPKs==
+===One of the first proteins known to be phosphorylated by ERK was a [[microtubule-associated protein]] (MAP)===
+===Regulation of translation and transcription===
+One effect of MAPK activation is to alter the translation of mRNA to proteins.
+====MAPK phosphorylates the 40S [[ribosomal protein S6 kinase]] (RSK). RSK phosphorylates [[ribosomal protein S6]].====
+====MAPK can phosphorylate [[C-myc]]====
+====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), 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>
 == References ==
 <references/>