TPL2 meets p38MAPK: emergence of a novel positive feedback loop in inflammation.
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 TNFα 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 TGFβ-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 TNFα biosynthesis and is also essential for TNF-receptor 1 signalling. Hence, a new signalling pathway from TAK1 via IκB kinase, p105 NFκB 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.
Institute of Physiological Chemistry, Hannover Medical University, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Manoj B
MB
Menon
Institute of Physiological Chemistry, Hannover Medical University, Carl-Neuberg-Str. 1, Hannover 30625, Germany.
Matthias
M
Gaestel
D000818:Animals; D006801:Humans; D007249:Inflammation / Q000201:enzymology / Q000378:metabolism*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D011518:Proto-Oncogene Proteins; D048051:p38 Mitogen-Activated Protein Kinases; D020930:MAP Kinase Kinase Kinases; C069937:MAP3K8 protein, human
Toll-like receptors; mitogen-activated protein kinases; stress kinases; tumour necrosis factors