The p38 Mitogen-activated Protein Kinases (MAPKs) are a family of four related Ser/Thr kinases activated by proinflammatory cytokines and environmental stresses, such as UV irradiation and heat shock. Stress signals are delivered to this cascade by members of small GTPases of the Rho family (Rac, Rho, Cdc42). p38 MAPK is involved in the regulation of Hsp27 and MAPKAP-2 and several transcription factors including ATF2, STAT1, and indirectly CREB via activation of MSK1. The p38 MAPK protein also plays a role in cell differentiation, autophagy and apoptosis. Mkk3 and SEK can activate p38 MAPK by phosphorylation at Thr180 and Tyr182, which in turn activates the MAPKAP kinase 2 and regulating phosphorylation of ATF2, Mac and MEF2.
Widely expressed with a maximal expression in lung and kidney.In vitro, phosphorylates MBP.
Mitogen-activated protein kinase 9 (MAPK9), also well known as c-Jun N-terminal kinase (JNK2), is a member of MAP kinase subfamily belonging to the protein kinase superfamily. The crystal structure of human JNK2 complexed with an indazole inhibitor by applying a high-throughput protein engineering and surface-site mutagenesis approach. A novel conformation of the activation loop is observed, which is not compatible with its phosphorylation by upstream kinases. This activation inhibitory conformation of JNK2 is stabilized by the MAP kinase insert that interacts with the activation loop in an induced-fit manner. It suggest that the MAP kinase insert of JNK2 plays a role in the regulation of JNK2 activation, possibly by interacting with intracellular binding partners. JNK2 deficiency leads to reduced c-Jun degradation, thereby augmenting c-Jun levels and cellular proliferation, and suggests that JNK2 is a negative regulator of cellular proliferation in multiple cell types. JNK2 blocks the ubiquitination of tumor suppressor p53, and thus increases the stability of p53 in nonstressed cells. JNK2 negatively regulates antigen-specific CD8+ T cell expansion and effector function, and thus selectively blocking JNK2 in CD8+ T cells may potentially enhance anti-tumor immune response. Lack of JNK2 expression was associated with higher tumor aneuploidy and reduced DNA damage response. Additionally,the JNK2 protein could be a novel therapeutic target in dry eye disease, and may provide a novel target for prevention of vascular disease and atherosclerosis.
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