title: ERK1/2 MAP kinases: structure, function, and regulation.
abstract: ERK1 and ERK2 are related protein-serine/threonine kinases that participate in the Ras-Raf-MEK-ERK signal transduction cascade. This cascade participates in the regulation of a large variety of processes including cell adhesion, cell cycle progression, cell migration, cell survival, differentiation, metabolism, proliferation, and transcription. MEK1/2 catalyze the phosphorylation of human ERK1/2 at Tyr204/187 and then Thr202/185. The phosphorylation of both tyrosine and threonine is required for enzyme activation. Whereas the Raf kinase and MEK families have narrow substrate specificity, ERK1/2 catalyze the phosphorylation of hundreds of cytoplasmic and nuclear substrates including regulatory molecules and transcription factors. ERK1/2 are proline-directed kinases that preferentially catalyze the phosphorylation of substrates containing a Pro-Xxx-Ser/Thr-Pro sequence. Besides this primary structure requirement, many ERK1/2 substrates possess a D-docking site, an F-docking site, or both. A variety of scaffold proteins including KSR1/2, IQGAP1, MP1, β-Arrestin1/2 participate in the regulation of the ERK1/2 MAP kinase cascade. The regulatory dephosphorylation of ERK1/2 is mediated by protein-tyrosine specific phosphatases, protein-serine/threonine phosphatases, and dual specificity phosphatases. The combination of kinases and phosphatases make the overall process reversible. The ERK1/2 catalyzed phosphorylation of nuclear transcription factors including those of Ets, Elk, and c-Fos represents an important function and requires the translocation of ERK1/2 into the nucleus by active and passive processes involving the nuclear pore. These transcription factors participate in the immediate early gene response. The activity of the Ras-Raf-MEK-ERK cascade is increased in about one-third of all human cancers, and inhibition of components of this cascade by targeted inhibitors represents an important anti-tumor strategy. Thus far, however, only inhibition of mutant B-Raf (Val600Glu) has been found to be therapeutically efficacious.
authors.affiliation: Blue Ridge Institute for Medical Research, 3754 Brevard Road, Suite 116, Box 19, Horse Shoe, NC 28742, USA. rrj@brimr.org
authors.forename: Robert
authors.initials: R
authors.lastname: Roskoski
mesh_terms: D000818:Animals; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000378:metabolism*; D010749:Phosphoprotein Phosphatases / Q000378:metabolism; D011487:Protein Conformation; D047428:Protein Kinase Inhibitors / Q000494:pharmacology
chemical_list: D047428:Protein Kinase Inhibitors; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D010749:Phosphoprotein Phosphatases