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TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase.
Pattison, Michael J; Mitchell, Olivia; Flynn, Helen R; Chen, Chao-Sheng; Yang, Huei-Ting; Ben-Addi, Hakem; Boeing, Stefan; Snijders, Ambrosius P; Ley, Steven C.
Affiliation
  • Pattison MJ; The Francis Crick Institute, Immune Signalling Laboratory, Mill Hill Laboratory, London NW7 1AA, U.K.
  • Mitchell O; The Francis Crick Institute, Immune Signalling Laboratory, Mill Hill Laboratory, London NW7 1AA, U.K.
  • Flynn HR; The Francis Crick Institute, Protein Analysis and Proteomics Laboratory, Clare Hall Laboratory, South Mimms EN6 3LD, U.K.
  • Chen CS; The Francis Crick Institute, Immune Signalling Laboratory, Mill Hill Laboratory, London NW7 1AA, U.K.
  • Yang HT; The Francis Crick Institute, Immune Signalling Laboratory, Mill Hill Laboratory, London NW7 1AA, U.K.
  • Ben-Addi H; The Francis Crick Institute, Immune Signalling Laboratory, Mill Hill Laboratory, London NW7 1AA, U.K.
  • Boeing S; The Francis Crick Institute, Bioinformatics and Biostatistics Service, Lincoln's Inn Fields Laboratory, London WC2A 3LY, U.K.
  • Snijders AP; The Francis Crick Institute, Protein Analysis and Proteomics Laboratory, Clare Hall Laboratory, South Mimms EN6 3LD, U.K.
  • Ley SC; The Francis Crick Institute, Immune Signalling Laboratory, Mill Hill Laboratory, London NW7 1AA, U.K.
Biochem J ; 473(18): 2845-61, 2016 09 15.
Article in En | MEDLINE | ID: mdl-27402796
Previous studies suggested that Toll-like receptor (TLR) stimulation of the p38α MAP kinase (MAPK) is mediated by transforming growth factor-ß-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 IκB kinase (IKK) phosphorylation of the TPL-2 binding partner nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB1) 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-κB1 p105. Owing to redundancy of MKK3/6 with MKK4, Map3k8(D270A) mutation only fractionally decreased lipopolysaccharide activation of p38α. TNF activation of p38α, which is mediated predominantly via MKK3/6, was substantially reduced. TPL-2 catalytic activity was also required for MKK3/6 and p38α activation following macrophage stimulation with Mycobacterium tuberculosis and Listeria monocytogenes Our experiments demonstrate that the IKK/NF-κB1 p105/TPL-2 signalling pathway, downstream of TAK1, regulates MKK3/6 and p38α activation in macrophages in inflammation.
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Kinases / Receptors, Tumor Necrosis Factor, Type I / Toll-Like Receptors / Macrophages Limits: Animals Language: En Journal: Biochem J Year: 2016 Type: Article
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Full text: 1 Collection: 01-internacional Database: MEDLINE Main subject: Protein Kinases / Receptors, Tumor Necrosis Factor, Type I / Toll-Like Receptors / Macrophages Limits: Animals Language: En Journal: Biochem J Year: 2016 Type: Article