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Deprecated: Implicit conversion from float 231.6 to int loses precision in C:\Inetpub\vhosts\kidney.de\httpdocs\pget.php on line 534 Biochem+J 2016 ; 473 (18): 2845-61 Nephropedia Template TP
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TLR and TNF-R1 activation of the MKK3/MKK6?p38? axis in macrophages is mediated by TPL-2 kinase #MMPMID27402796
Pattison MJ; Mitchell O; Flynn HR; Chen CS; Yang HT; Ben-Addi H; Boeing S; Snijders AP; Ley SC
Biochem J 2016[Sep]; 473 (18): 2845-61 PMID27402796show ga
Previous studies suggested that Toll-like receptor (TLR) stimulation of the p38? MAP kinase (MAPK) is mediated by transforming growth factor-?-activated kinase 1 (TAK1) activation of MAPK kinases, MKK3, MKK4 and MKK6. We used quantitative mass spectrometry to monitor tumour progression locus 2 (TPL-2)-dependent protein phosphorylation following TLR4 stimulation with lipopolysaccharide, comparing macrophages from wild-type mice and Map3k8D270A/D270A mice expressing catalytically inactive TPL-2 (MAP3K8). In addition to the established TPL-2 substrates MKK1/2, TPL-2 kinase activity was required to phosphorylate the activation loops of MKK3/6, but not of MKK4. MKK3/6 activation required I?B kinase (IKK) phosphorylation of the TPL-2 binding partner nuclear factor ?-light-chain-enhancer of activated B cells (NF-?B1) p105, similar to MKK1/2 activation. Tumour necrosis factor (TNF) stimulation of MKK3/6 phosphorylation was similarly dependent on TPL-2 catalytic activity and IKK phosphorylation of NF-?B1 p105. Owing to redundancy of MKK3/6 with MKK4, Map3k8D270A mutation only fractionally decreased lipopolysaccharide activation of p38?. TNF activation of p38?, which is mediated predominantly via MKK3/6, was substantially reduced. TPL-2 catalytic activity was also required for MKK3/6 and p38? activation following macrophage stimulation with Mycobacterium tuberculosis and Listeria monocytogenes. Our experiments demonstrate that the IKK/NF-?B1 p105/TPL-2 signalling pathway, downstream of TAK1, regulates MKK3/6 and p38? activation in macrophages in inflammation.