the activation loop by dual specificity kinases of the middle MAP2K tier specific for the p38 MAPK cascade: Map2k3 and Map2k6 known as Mkk3 and Mkk6, respectively. The two kinases differentially activate the p38 isoforms in response to various upstream stimuli. Depending on conditions or cell type, Mapk14 or p38 alpha can also be phosphorylated by Map2k4 or Mkk4; a c-Jun N-terminal kinase (JNK) specific second tier kinase. To accomplish their function, the second tier kinases need to be activated by the upstream MAP3K tier. Several MAP3K can activate p38 pathway and while some appear to be p38 specific, others can also activate JNK and/or Erk5 MAPK pathways. Activation of the upstream tier is complex; it can involve members of the small monomeric G proteins, such as Rac1 and receptor associated factors such as Traf2 or Traf6. Of the four p38 MAPKs, Mapk14/p38 alpha and Mapk11/p38 beta have been the better characterized members. Scaffold proteins mediate the organization of components and regulate the functioning of the pathway. Some, like the Ccm2 scaffold known as Osm, appear to be p38 specific; Ccm2 forms a complex with Rac1 - a small monomeric G protein of the Rho family, Map3k3/Mekk3 and Map2k3/Mkk3 to activate Mapk14/p38 alpha in response to osmotic shock. Others, like Spag9, known as JLP or Jip4 and a member of a family of JNK specific scaffolds, can promote p38 activation via the upstream Map3k5/Ask1 and Map3k7/Tak1 kinases and is dependent on the presence of Cdon known as Cdo, a cell surface molecule and a positive regulator of myogenesis. The cytoplasmic tail of Cdon interacts with Spag9. It also interacts with Bnip2 which in turn interacts with Cdc42, another member of the Rho family, and the formation of the complex is important for the activation of p38 pathway. Phosphatases, like PP2C or dual specificity Dups/Mkp phosphatases negatively regulate the pathway. Ppm1d known as Wip1, a serine/threonine phosphatase of PP2C down-regulates Mapk14/p38 alpha activity as well as the activity of many other target proteins. Members of Dusp/Mkp dephosphorylate both Mapk14/p38 alpha and Mapk11/p38 beta. In addition to the canonical pathway here described, Mapk14/p38 alpha and possibly Mapk14/p38 beta, might be activated via alternative mechanisms bypassing the second tier kinases. The p38 MAPKs are serine/threonine kinases whose many substrates include both cytoplasmic proteins and nuclear transcription factors. In addition, p38 pathway can activate other kinases that further transmit the signal; collectively they are known as MAPKAPK and effectively constitute an additional tier. Mapk14/p38 alpha and Mapk11/p38 beta appear to be the only ones activating the MAPKAPKs and most of the currently known targets of p38 cascade are substrates of these two p38 MAPKs. Structures of the Mapk14/p38 alpha in complex with MAPK binding domain of Dusp10/Mkp5 click to access the PDB page and in complex with Mapkapk2 substrate click to access this PDB page have been solved by X-ray crystallography. Processes regulated by the p38 pathway include differentiation, migration, inflammatory response; deregulation of the pathway has been primarily associated with inflammation and cardiovascular dysfunction. .To see the ontology report for annotations, Gviewer and download, click here ....(less)