inases of the middle MAP2K tier (here Mkk4 and Mkk7 - Map2k4 and 7, respectively), in turn activated by the upstream MAP3K tier. Interestingly, 14 out of about 20 Map3ks can activate the Mkk4/7 middle tier. While some are specific for Jnk pathway, others can activate both Jnk and the p38 MAPK pathway (the other SAPK), a few activate both Jnk and either Raf/Mek/Erk or Erk5 MAPK pathways. Some of Map3ks may be activated by small monomeric G-proteins, particularly by members of the Rho family (eg. Rac1 and Cdc42); others by interaction with adapter bound proteins downstream of cytokine receptors (eg. Traf2). Out of the three Jnk genes of the MAPK tier, two are ubiquitously expressed (Mapk8/Jnk1 and Mapk9/Jnk2) while Mapk10/Jnk3 appears to be restricted only to certain tissues. The MAPKs are serine/threonine kinases with a broad repertoire of targets that include transcription factors and other nuclear proteins; among the non-nuclear targets there are members of the intrinsic apoptotic pathway and structural proteins. Several scaffold proteins mediate the organization of components and regulate the functioning of the pathway. The family of Jip proteins has been shown to act as scaffolds for Jnk; the second member might also act as a scaffold for p38 Mapk cascade. They use their C-terminal regions to interact with kinases of the first and second tier and N-terminal regions to interact with Mapks of the last tier (schematically represented in the diagram). Dual specificity phosphatases such as Dusp8/M3/6, Dusp10/Mkp-5, Dusp16/Mkp-7 and possibly Dusp1/Mkp-1 negatively regulate the pathway but the exact mechanisms thereby this is accomplished are still elusive. Some Mkp members are inactive in the absence of the substrate. Binding of the substrate alters the structure of the DUSP (DSPc domain) phosphatase domain, rendering the enzyme catalytically active. Dusp8, 10 and 16 are type III family members that localize both in the cytoplasm and nucleus. Processes regulated by JNK pathway include proliferation, motility, inflammatory response, apoptosis; deregulation of the pathway is associated with several human diseases.To see the ontology report for annotations, GViewer and download, click here
[click to see related GO term ¿ GO:0007254 and KEGG map ¿ map04010...(less)