MAPK/ERK pathway

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

Epidermal Growth Factor Receptor (EGFR; see also Epidermal growth factor). EGFR belongs to Receptor tyrosine kinases, class I.

Trk A/B: High affinity nerve growth factor receptor (TrkA). TrkB tyrosine kinase receptor. See also Neurotrophin.

Fibroblast growth factor receptor

Platelet-derived growth factors and receptors

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

Ras activation

GTPase KRas

Allosteric modulation of H-Ras GTPase.

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^[1]. 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^[2]. For details on c-Raf see Molecular Playground/C-Raf.

Mitogen-activated protein kinase kinase kinase

MAPKs

• Mitogen-activated protein kinase kinase
• Mitogen-activated protein kinase
• Michael Roberts/BIOL115/ERK2
• 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 inhibitor

• 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.