Studies On Tpl2-MEK1/2-ERK1/2 Signaling Pathway

Inflammation is important in infection control and tissue damage repair.Innate immune cells recognize PAMPs by PRRs and activate inflammatory pathways such as NF-κB and MAPK pathways to initiate inflammatory responses.ERK1/2 MAPK signaling pathway is involved in the regulation of cell cycle progression and the production of proinflammatory cytokines,abnormal activation of which may promote the development of tumor and inflammatory diseases.Inflammatory signaling-induced ERK1/2 activation depends on the MAPKKK(MAP3K)kinase Tpl2.Although Tpl2 is essential for ERK1/2 activation by proinflammatory cytokines,the biochemical mechanism by which Tpl2 is activated is not fully understood.In this study,we characterized Tpl2-MEK1/2-ERK1/2 pathway activation.We reconstitued a system,namely TRAF6-based Tpl2-MEK1/2-ERK1/2 activation in vitro.By using cell-based and cell-free systems,we found that Tpl2-MEK1/2-ERK1/2 activation by proinflammatory cytokines TNF-α and IL-β depends on TAK1,IKK and ubiquitination.Thus,we preliminarily explained the biochemical mechanism of Tpl2 activation and proved that IKK can induce both NF-κB and ERK1/2 signaling pathway activation by using the traditional biochemical strategies.In addition,Tpl2-MEK1/2-ERK1/2 signaling pathway regulates the production of proinflammatory cytokines TNFα.The potential of Tpl2,as an anti-inflammatory drugs target for treatment of certain types of inflammatory diseases and cancer,is considerable,but the inhibitors of Tpl2 are rare in fact.Therefore,we tested a small kinase inhibitor library to carry out the preliminary screening for potential inhibitors of Tpl2,and found two kinds of small molecule inhibitors with the further development value.