ArticleThe Biochemical journal2016
TLR and TNF-R1 activation of the MKK3/MKK6-p38α axis in macrophages is mediated by TPL-2 kinase.
Article in The Biochemical journal, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 37 papers.
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37 citing papers in PubMed, 60 citations in OpenAlex.
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- Resiquimod induces a mixed Th1 and Th2 response via STAT1 and STAT3 signalling in chickens.Biochemistry and biophysics reports · 2025Article
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- Dynamical and combinatorial coding by MAPK p38 and NFκB in the inflammatory response of macrophages.Molecular systems biology · 2024Article
- The Influenza-Induced Pulmonary Inflammatory Exudate in Susceptible Tpl2-Deficient Mice Is Dictated by Type I IFN Signaling.Inflammation · 2023Article
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- ERK1/2 in immune signalling.Biochemical Society transactions · 2022Review
- TPL2 kinase expression is regulated by the p38γ/p38δ-dependent association of aconitase-1 withProceedings of the National Academy of Sciences of the United States of America · 2022Article
- Effects of Human RelA Transgene on Murine Macrophage Inflammatory Responses.Biomedicines · 2022Article
- TPL-2 Inhibits IFN-β Expression via an ERK1/2-TCF-FOS Axis in TLR4-Stimulated Macrophages.Journal of immunology (Baltimore, Md. : 1950) · 2022Article
- IKBKE-driven TPL2 and MEK1 phosphorylations sustain constitutive ERK1/2 activation in tumor cells.EXCLI journal · 2022Article
- New Druggable Targets for Rheumatoid Arthritis Based on Insights From Synovial Biology.Frontiers in immunology · 2022Review
- OncogenicCancers · 2021Review
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- TPL-2 kinase induces phagosome acidification to promote macrophage killing of bacteria.The EMBO journal · 2021Article
- IL-3 is essential for ICOS-L stabilization on mast cells, and sustains the IL-33-induced RORγtImmunology · 2021Article
- Foot-and-Mouth Disease Virus Structural Protein VP1 Destroys the Stability of TPL2 Trimer by Degradation TPL2 to Evade Host Antiviral Immunity.Journal of virology · 2021Article
- Article
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9 authors at 1 institution in 1 country.
Funding
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 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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