MAPKs are a group of protein Serine/threonine Kinases that are activated in response to a variety of extracellular stimuli and mediate signal transduction from the cell surface to the nucleus. In combination with several other signaling pathways, they can differentially alter phosphorylation status of numerous proteins, including Transcription Factors, Cytoskeletal proteins, Kinases and other Enzymes, and greatly influence Gene Expression, Metabolism, Cell Division, Cell Morphology and Cell Survival. Furthermore, epigenetic aberrations of these enzymes or of the signaling cascades that regulate them have been implicated in a variety of human diseases including Cancer, Inflammation and Cardiovascular disease. There are four major groups of MAPKs in mammalian cells—the ERKs (Extracellular signal-Regulated Kinases), the p38MAPKs, the JNKs (c-Jun NH2-terminal Kinases) and the ERK5 (Extracellular signal-Regulated Kinase-5) or BMK cascades. These MAPKs are activated by dual phosphorylation at the tripeptide motif Thr-Xaa-Tyr. The sequence of this tripeptide motif is different in each group of MAPKs: ERK (Thr-Glu-Tyr); p38 (Thr-Gly-Tyr); and JNK (Thr-Pro-Tyr). Each MAPK pathway contains a three-tiered kinase cascade comprising a MAPKKK/MAP3K/MEKK/MKKK (MAP Kinase Kinase Kinase), a MAPKK/MAP2K/MEK/MKK (MAP Kinase Kinase) and the MAPK. This three-tier module mediates ultrasensitive switch-like responses to stimuli. Frequently, a MAPKKKK, MAP4K or MKKKK (MAPKKK Kinase) activates the MAPKKK. The MAPKKKs then phosphorylates a dual-specificity protein kinase MAPKK, which in turn phosphorylates the MAPK (Ref.1 & 2). References:
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