| First Author | Menon MB | Year | 2016 |
| Journal | Biochem J | Volume | 473 |
| Issue | 19 | Pages | 2995-9 |
| PubMed ID | 27679858 | Mgi Jnum | J:245080 |
| Mgi Id | MGI:5917802 | Doi | 10.1042/BCJ20160672C |
| Citation | Menon MB, et al. (2016) TPL2 meets p38MAPK: emergence of a novel positive feedback loop in inflammation. Biochem J 473(19):2995-9 |
| abstractText | The activation of p38(MAPK) by Toll-like receptor signalling is essential for the inflammatory response of innate immunity due to its role in post-transcriptional regulation of TNFalpha and cytokine biosynthesis. p38(MAPK) activation proceeds by the upstream MAP2Ks, MAPK kinase (MKK)3/6 as well as MKK4, which in turn are substrates for MAP3Ks, such as TGFbeta-activated protein kinase-1 (TAK1). In contrast, TPL2 has been described as an exclusive MAP3K of MKK1/2-triggering activation of the classical ERKs, ERK1/2. In the recent issue of the Biochemical Journal, Pattison et al report their screening for TPL2 substrates in LPS-stimulated macrophages and the identification of MKK3/6. Using catalytic-dead TPL2 (Map3k8(D270A/D270A)) knockin macrophages, they demonstrated that activation of MKK3/6 by TPL2 significantly contributes to LPS-dependent TNFalpha biosynthesis and is also essential for TNF-receptor 1 signalling. Hence, a new signalling pathway from TAK1 via IkappaB kinase, p105 NFkappaB and TPL2 to MKK3/6 and p38(MAPK) is established in macrophages. Taking into account that some isoforms of p38(MAPK) are necessary for maintaining functional steady-state levels of TPL2, a positive feedback loop in inflammation emerges. |
