The MAPK (Mitogen-Activated Protein Kinase) pathway is one of the primordial signaling systems that nature has used in several permutations to accomplish an amazing variety of tasks. It exists in all eukaryotes, and controls such fundamental cellular processes as Proliferation, Differentiation, Survival and Apoptosis. Mammalian MAPK can be divided into four groups based on their structure and function: ERKs (Extracellular signal-Regulated Kinases), p38MAPKs, JNKs (c-Jun NH2-terminal Kinases) and ERK5 (Extracellular signal-Regulated Kinase-5) or BMK. Activation of these MAPKs occurs through a cascade of upstream kinases; a MAPKKK (MAPK Kinase Kinase) first phosphorylates a dual-specificity protein kinase MAPKK (MAPK Kinase), which in turn phosphorylates the MAPK. This set-up provides not only for signal amplification, but, maybe even more importantly, for additional regulatory interfaces that allow the kinetics, duration and amplitude of the activity to be precisely tuned. ERK, a member of the MAPK family, have been established as major participants in the regulation of cell growth and differentiation, but when improperly activated contribute to malignant transformation. ERK1 and 2 form a central component in the MAPK cascade. The MAPK/ERK signaling cascade is activated by a wide variety of receptors involved in growth and differentiation including GPCRs (G-Protein Coupled Receptors), RTKs (Receptor Tyrosine Kinases), Integrins, and Ion channels. The specific components of the cascade vary greatly among different stimuli, but the architecture of the pathway usually includes a set of adaptors like SHC, GRB2 (Growth Factor Receptor Bound protein-2), Crk, etc. linking the receptor to a GEF (Guanine nucleotide Exchange Factor) like SOS (Son of Sevenless), C3G, etc. transducing the signal to small GTP binding proteins (Ras, Rap1), which in turn activate the core unit of the cascade composed of a MAPKKK (Raf), a MAPKK (MEK1/2 (MAPK/ERK Kinase-1/2)) and MAPK (ERK). An activated ERK dimer can regulate targets in the cytosol and also translocate to the nucleus where it phosphorylates a variety of transcription factors regulating gene expression (Ref.1 & 2).
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