Regulation and function of TPL-2, an IkB kinase-regulated MAP kinase kinase kinase  

出　　处：《Cell Research》2011年第1期131-145,共15页细胞研究（英文版）

摘　　要：The IkB kinase （IKK） complex plays a well-documented role in innate and adaptive immunity. This function has been widely attributed to its role as the central activator of the NF-kB family of transcription factors. However, another important consequence of IKK activation is the regulation of TPL-2, a MEK kinase that is required for activation of ERK-1/2 MAP kinases in myeloid cells following Toll-like receptor and TNF receptor stimulation. In unstimulated cells, TPL-2 is stoichiometrically complexed with the NF-kB inhibitory protein NF-kB1 p105, which blocks TPL-2 access to its substrate MEK, and the ubiquitin-binding protein ABIN-2 （A20-binding inhibitor of NF-kB 2）, both of which are required to maintain TPL-2 protein stability. Following agonist stimulation, the IKK complex phosphorylates p105, triggering its K48-linked ubiquitination and degradation by the proteasome. This releases TPL-2 from pl05-mediated inhibition, facilitating activation of MEK, in addition to modulating NF-kB activation by liberating associated Rel subunits for translocation into the nucleus. IKK-induced proteolysis of p105, therefore, can directly regulate both NF-kB and ERK MAP kinase activation via NF-kB1 p105. TPL-2 is critical for production of the proinflammatory cytokine TNF during inflammatory responses. Consequently, there has been considerable interest in the pharmaceutical industry to develop selective TPL-2 inhibitors as drugs for the treatment of TNF-dependent inflammatory diseases, such as rheumatoid arthritis and inflammatory bowel disease. This review summarizes our current understanding of the regulation of TPL-2 signaling function, and also the complex positive and negative roles of TPL-2 in immune and inflammatory responses.

关 键 词：ABIN-2 COT IKK MAP3K8 MAP kinase TLR TPL-2 NF-kB p105 

分 类 号：Q945.78[生物学—植物学] Q513.2