ArticleThe Journal of biological chemistry2012
TRAF6 protein couples Toll-like receptor 4 signaling to Src family kinase activation and opening of paracellular pathway in human lung microvascular endothelia.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 27 papers.
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Who cites it
27 citing papers in PubMed, 49 citations in OpenAlex.
- Hantaan virus activates Src family kinase and induces endothelial cell hyperpermeability via the TLR4/TRAF6 pathway.Journal of medical microbiology · 2025Article
- IFNγ regulates MR1 transcription and antigen presentation.Frontiers in immunology · 2025Article
- Therapeutic targeting of full-length interleukin-33 protein levels with cell-permeable decoy peptides attenuates fibrosis in the bleomycin model in vivo.The Journal of pharmacology and experimental therapeutics · 2025Article
- The myosin II inhibitor, blebbistatin, ameliorates pulmonary endothelial barrier dysfunction in acute lung injury induced by LPS via NMMHC IIA/Wnt5a/β-catenin pathway.Toxicology and applied pharmacology · 2022Article
- Article
- Tril dampens Nodal signaling through Pellino2- and Traf6-mediated activation of Nedd4l.Proceedings of the National Academy of Sciences of the United States of America · 2021Article
- Tau Ubiquitination in Alzheimer's Disease.Frontiers in neurology · 2021Review
- Protein Arginine Methyltransferase 1 (PRMT1) Selective Inhibitor, TC-E 5003, Has Anti-Inflammatory Properties in TLR4 Signaling.International journal of molecular sciences · 2020Article
- Article
- Src Family Kinases Regulate Interferon Regulatory Factor 1 K63 Ubiquitination following Activation by TLR7/8 Vaccine Adjuvant in Human Monocytes and B Cells.Frontiers in immunology · 2018Article
- EETs reduces LPS-induced hyperpermeability by targeting GRP78 mediated Src activation and subsequent Rho/ROCK signaling pathway.Oncotarget · 2017Article
- Novel Noncatalytic Substrate-Selective p38α-Specific MAPK Inhibitors with Endothelial-Stabilizing and Anti-Inflammatory Activity.Journal of immunology (Baltimore, Md. : 1950) · 2017Article
- Biological and pathophysiological roles of end-products of DHA oxidation.Biochimica et biophysica acta. Molecular and cell biology of lipids · 2017Review
- Article
- Molecular Mechanisms Regulating LPS-Induced Inflammation in the Brain.Frontiers in molecular neuroscience · 2016Article
- The intracerebroventricular injection of rimonabant inhibits systemic lipopolysaccharide-induced lung inflammation.Journal of neuroimmunology · 2015Article
- The Role of TLR4 and Fyn Interaction on Lipopolysaccharide-Stimulated PAI-1 Expression in Astrocytes.Molecular neurobiology · 2015Article
- Co-operation of TLR4 and raft proteins in LPS-induced pro-inflammatory signaling.Cellular and molecular life sciences : CMLS · 2015Review
- EGFR phosphorylation of DCBLD2 recruits TRAF6 and stimulates AKT-promoted tumorigenesis.The Journal of clinical investigation · 2014Article
- The adaptor CRADD/RAIDD controls activation of endothelial cells by proinflammatory stimuli.The Journal of biological chemistry · 2014Article
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Authors and funding
13 authors at 4 institutions in 1 country.
Funding
Abstract
Gram-negative bacteria release lipopolysaccharide (LPS) into the bloodstream. Here, it engages Toll-like receptor (TLR) 4 expressed in human lung microvascular endothelia (HMVEC-Ls) to open the paracellular pathway through Src family kinase (SFK) activation. The signaling molecules that couple TLR4 to the SFK-driven barrier disruption are unknown. In HMVEC-Ls, siRNA-induced silencing of TIRAP/Mal and overexpression of dominant-negative TIRAP/Mal each blocked LPS-induced SFK activation and increases in transendothelial [(14)C]albumin flux, implicating the MyD88-dependent pathway. LPS increased TRAF6 autoubiquitination and binding to IRAK1. Silencing of TRAF6, TRAF6-dominant-negative overexpression, or preincubation of HMVEC-Ls with a cell-permeable TRAF6 decoy peptide decreased both LPS-induced SFK activation and barrier disruption. LPS increased binding of both c-Src and Fyn to GST-TRAF6 but not to a GST-TRAF6 mutant in which the three prolines in the putative Src homology 3 domain-binding motif (amino acids 461-469) were substituted with alanines. A cell-permeable decoy peptide corresponding to the same proline-rich motif reduced SFK binding to WT GST-TRAF6 compared with the Pro → Ala-substituted peptide. Finally, LPS increased binding of activated Tyr(P)(416)-SFK to GST-TRAF6, and preincubation of HMVEC-Ls with SFK-selective tyrosine kinase inhibitors, PP2 and SU6656, diminished TRAF6 binding to c-Src and Fyn. During the TRAF6-SFK association, TRAF6 catalyzed Lys(63)-linked ubiquitination of c-Src and Fyn, whereas SFK activation increased tyrosine phosphorylation of TRAF6. The TRAF6 decoy peptide blocked both LPS-induced SFK ubiquitination and TRAF6 phosphorylation. Together, these data indicate that the proline-rich Src homology 3 domain-binding motif in TRAF6 interacts directly with activated SFKs to couple LPS engagement of TLR4 to SFK activation and loss of barrier integrity in HMVEC-Ls.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.