| First Author | Pattison MJ | Year | 2016 |
| Journal | Biochem J | Volume | 473 |
| Issue | 18 | Pages | 2845-61 |
| PubMed ID | 27402796 | Mgi Jnum | J:245111 |
| Mgi Id | MGI:5919807 | Doi | 10.1042/BCJ20160502 |
| Citation | Pattison MJ, et al. (2016) TLR and TNF-R1 activation of the MKK3/MKK6-p38alpha axis in macrophages is mediated by TPL-2 kinase. Biochem J 473(18):2845-61 |
| abstractText | Previous studies suggested that Toll-like receptor (TLR) stimulation of the p38alpha MAP kinase (MAPK) is mediated by transforming growth factor-beta-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 Map3k8(D270A/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 IkappaB kinase (IKK) phosphorylation of the TPL-2 binding partner nuclear factor kappa-light-chain-enhancer of activated B cells (NF-kappaB1) 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-kappaB1 p105. Owing to redundancy of MKK3/6 with MKK4, Map3k8(D270A) mutation only fractionally decreased lipopolysaccharide activation of p38alpha. TNF activation of p38alpha, which is mediated predominantly via MKK3/6, was substantially reduced. TPL-2 catalytic activity was also required for MKK3/6 and p38alpha activation following macrophage stimulation with Mycobacterium tuberculosis and Listeria monocytogenes Our experiments demonstrate that the IKK/NF-kappaB1 p105/TPL-2 signalling pathway, downstream of TAK1, regulates MKK3/6 and p38alpha activation in macrophages in inflammation. |
