Erk

ERK, the acronym for "Extracellular-signal Regulated Kinase" comprises an evolutionary conserved family of kinases (enzymes) of which 8 isoforms (ERK 1-8) are known so far.

The "Extracellular-signal Regulated Kinases" belong to the mitogen-activated kinases (MAP kinases). They belong, according to their modified groups, to the serine/threonine kinases. ERK kinases are essential components of the superior MAPK signalling pathway. The MAPK signaling cascade (RAS→ BRAF → → MEK→ ERK→ cell proliferation / cell differentiation), which takes place intracellularly and is connected in series, is a fundamental cell biological process through which the vital cell functions "proliferation and differentiation" are decisively regulated.

ERK (phospho-ERK) phosphorylated by the kinase MEK1/2 translocates into the cell nucleus and activates cyclin D1 (CCND1), which in turn binds to CDK4/6 (Note: MEK1/2 are the only known activators of ERK1/2).

This complex posphorylates the retinoblastoma protein RB1. Normally, RB1 binds the transcription factor E2F and inactivates it. However, the activation (phosphorylation) of RB1 leads to a dissociation of the E2F complex. Free E2E acts as a transcription factor for a number of genes that are responsible for cell proliferation and cell metabolism (Held L et al. 2011)

The MAPk signaling path can be inhibited at various points:

• BRAF → MEK by the selective BRAF inhibitors -vemurafenib/dabrafenib and by non-selective BRAF inhibitors like sorafenib;
• MEK→ ERK by the MEK inhibitors selumetinib and trametinib.

The efficiency of ERK inhibitors on tumor growth (e.g. in malignant melanoma) is not yet understood.

In animal experiments, the course of epilepsy could be positively influenced by inhibition of ERK activity.

In animal experiments it has also been shown in cocaine addiction that the desire for the drug was increased by activating ERK.

1. Carlino MS et al. (2014) Differential activity of MEK and ERK inhibitors in BRAF inhibitor resistant melanoma.Mol Oncol 8:544-554.
2. Held L et al (2011) Oncogenetics of melanoma: Basis for molecular diagnostics and therapy. J Deutsch Dermatol Ges 9: 510-517