sphorylation of threonine and tyrosine residues within a conserved TxY motif in the activation loop by dual specificity kinases MAP2Ks of the second tier, in turn activated by MAP3Ks serine/threonine kinases of the third tier. The MAPKs are serine/threonine kinases whose targets include transcription factors and regulators, other nuclear or cytoplasmic proteins, kinases collectively known as MAPKAPK that further transmit the signal. Docking interactions between members of the three tiers and with substrates and interactions with scaffold proteins assure the organization of distinct MAPK pathways and regulate the specificity of their signaling. Phosphatases and other regulatory proteins along with feedback loops act to shape these signaling cascades. Over the last 20 years, four major pathways have been characterized, together comprising 20 MAP3K, 7 MAP2K and 11 MAPK. The Raf/Mek/Erk pathway, also known as the extracellular signal regulated MAPK is a well studied and characterized pathway acting downstream of RTK via small G protein Ras activation. C-Jun N-terminal kinase (JNK) and p38 MAPKs pathways, known as the stress regulated MAPK cascades (SAPKs) are triggered by various stresses and are activated by adapters downstream of receptors for inflammatory cytokines. A subset of JNK can be triggered via small G protein Rho activation downstream of RTK or of G-protein coupled receptors (GPCR). Finally, the Erk5 pathway also known as the big MAP kinase, is activated by various stresses but not by inflammatory cytokines and, at least in Hela and PC12 cells, by growth factors....(less)