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TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase
- Source :
- Biochemical Journal
- Publication Year :
- 2016
-
Abstract
- Previous studies suggested that Toll-like receptor (TLR) stimulation of the p38α MAP kinase (MAPK) is mediated by transforming growth factor-β-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 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, Map3k8D270A 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.
- Subjects :
- 0301 basic medicine
MAPK/ERK pathway
Biochemistry & Molecular Biology
p38
IκB kinase
Biochemistry
p38 Mitogen-Activated Protein Kinases
Mass Spectrometry
03 medical and health sciences
Mice
0302 clinical medicine
TLR
Proto-Oncogene Proteins
Humans
Animals
Protein phosphorylation
Kinase activity
CHUK
Molecular Biology
Research Articles
11 Medical and Health Sciences
Inflammation
MAP kinase kinase kinase
biology
Kinase
IKK
Macrophages
Toll-Like Receptors
tumour necrosis factors
Cell Biology
06 Biological Sciences
MAP Kinase Kinase Kinases
Cell biology
Enzyme Activation
030104 developmental biology
NF-κB1
Receptors, Tumor Necrosis Factor, Type I
030220 oncology & carcinogenesis
Mitogen-activated protein kinase
biology.protein
03 Chemical Sciences
Protein Kinases
Research Article
TPL-2
Subjects
Details
- ISSN :
- 14708728
- Volume :
- 473
- Issue :
- 18
- Database :
- OpenAIRE
- Journal :
- The Biochemical journal
- Accession number :
- edsair.doi.dedup.....fbc03f27adf3ff66143f59a84e0262cd