A phosphorylation site in the Toll-like receptor 5 TIR domain is required for inflammatory signalling in response to flagellin

Ivison, Sabine; Khan, Mohammed A.; Graham, Nicholas R.; Bernales, Cecily Q.; Kaleem, Arnawaz; Tirling, Chelsea; Cherkasov, Artem; Steiner, Theodore S.

doi:10.1016/j.bbrc.2006.11.132

Cited by 31 publications

(35 citation statements)

References 15 publications

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“…Agonist engagement of TLR2, TLR3, TLR4, and TLR5 triggers their tyrosine phosphorylation, and mutations of several tyrosines in the TIR domains of these receptors impair TLR signaling (51)(52)(53)(54). In addition to TLRs, adapter proteins are subject to several posttranslational modifications.…”

Section: Discussionmentioning

confidence: 99%

“…TLR2, TLR3, TLR4, and TLR5 undergo agonist-induced tyrosine phosphorylation, and mutations of tyrosines within their TIR domains suppress TLR signaling capacities (51)(52)(53)(54) and alter recruitment of MyD88 to TLR4 and IRAK-1 activation at TLR4 (51). Tyrosine phosphorylation of Mal and serine phosphorylation and myristoylation of TRIF were found to regulate TLR signaling (55)(56)(57).…”

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confidence: 99%

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Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Piao

Song

Chen

et al. 2008

Journal of Biological Chemistry

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Section: Discussionmentioning

confidence: 99%

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confidence: 99%

Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Piao

Song

Chen

et al. 2008

Journal of Biological Chemistry

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“…Lysates were spun at 15,000 ϫ g for 10 min to pellet insoluble material, and supernatants were then spun at 100,000 ϫ g for 1 h to pellet membranes. Membrane proteins were immunoprecipitated with anti-V5 as described (18) and separated by SDS-PAGE. Gels were stained with SYPRO Ruby (Invitrogen Life Technologies) and the band corresponding to TLR5 (verified by its absence in identically treated cells not expressing TLR5) was excised, trypsinized in situ, and analyzed by liquid chromatography-single mass spectrometry at the Nucleic Acids and Protein Synthesis Core Mass Spectrometry facility at the University of British Columbia (Vancouver, British Columbia, Canada).…”

Section: Mass Spectrometric Identification Of Tlr5 Phosphorylationmentioning

confidence: 99%

Protein Kinase D Interaction with TLR5 Is Required for Inflammatory Signaling in Response to Bacterial Flagellin

Ivison

Graham

Bernales

et al. 2007

The Journal of Immunology

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Protein kinase D (PKD), also called protein kinase C (PKC)μ, is a serine-threonine kinase that is involved in diverse areas of cellular function such as lymphocyte signaling, oxidative stress, and protein secretion. After identifying a putative PKD phosphorylation site in the Toll/IL-1R domain of TLR5, we explored the role of this kinase in the interaction between human TLR5 and enteroaggregative Escherichia coli flagellin in human epithelial cell lines. We report several lines of evidence that implicate PKD in TLR5 signaling. First, PKD phosphorylated the TLR5-derived target peptide in vitro, and phosphorylation of the putative target serine 805 in HEK 293T cell-derived TLR5 was identified by mass spectrometry. Furthermore, mutation of serine 805 to alanine abrogated responses of transfected HEK 293T cells to flagellin. Second, TLR5 interacted with PKD in coimmunoprecipitation experiments, and this association was rapidly enhanced by flagellin treatment. Third, pharmacologic inhibition of PKC or PKD with Gö6976 resulted in reduced expression and secretion of IL-8 and prevented the flagellin-induced activation of p38 MAPK, but treatment with the PKC inhibitor Gö6983 had no significant effects on these phenotypes. Finally, involvement of PKD in the p38-mediated IL-8 response to flagellin was confirmed by small hairpin RNA-mediated gene silencing. Together, these results suggest that phosphorylation of TLR5 by PKD may be one of the proximal elements in the cellular response to flagellin, and that this event contributes to p38 MAPK activation and production of inflammatory cytokines in epithelial cells.

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“…In fact, Flic as adjuvant is able to bind to TLR5 on dendritic cells and macrophages. 12,13 So that, some signals are generated to activate adaptive immune system. 13,14 Some studies showed that VEGF could induce angiogenesis through effect on endothelial cells directly and also facilitate access oxygen and nutrients to tumor growth.…”

Section: Introductionmentioning

confidence: 99%

“…Todays, utilization of TLRs agonists is a method to increase vaccine efficacy. 13,14 Herein, type B pseudomonas aeruginosa recombinant FliC was used as adjuvant. In this study, Flic-E7d-HPV16, HPV16-E7d-Flic protein efficacy was investigated as vaccines in tumor bearing mice models.…”

Section: Introductionmentioning

confidence: 99%

HPV16E7d Candidate Vaccine Modified Genes Expression in Tumor Environment: Flic as Adjuvant Changed TGF-B Gene Expression

Mahdavi

Rakhshani

Riazi-Rad

2017

ACP

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Cervical cancer is one of the most important venereal disease and leads to mortality in women. Human papilloma virus causes this disease. This virus has three protein zones that includes of Early, Late and None coding areas. The early phase consists of E1 to E7 but E6 and E7 are two early oncoproteins of HPV which are responsible for disordering in cell cycle and tumor induction. In this study, the efficiency of FlicE7d-HPV16 and HPV16-E7d-Flic were investigated in tumor bearing Mice models .Tumor was induced in mice with transplantation method. After tumor growth, the mice were divided into five groups. two groups of C57BL/6 Mice were injected with 20µg of the vaccine Flic-E7d-HPV16 and E7d-HPV16-Flic subcutaneously three times with one week interval. The third group only E7d was injected and for fourth group only Flic was injected and for fifth group PBS was injected. One week after final immunization, tumor was assessed for gene expression and pathologic smear. According to pathological studies on the tumor samples of mice which indicated the tumor was kind of Sarcoma, Necrosis, Apoptosis, Mitosis and vessel generation were evaluated in each group. Apoptosis and angiogenesis in A, B group were not observed. According to investigation of TGF-β and VEGF genes and HPRT control gene using PCR-real-Time, there was a decrease of VEGF and TGF-β genes in group A and B. SO the vaccine of group A, B were potent in the reduction of angiogenesis. As a result, Flic as an adjuvant improved anti-tumor effect of HPV16 E7d vaccine.

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A phosphorylation site in the Toll-like receptor 5 TIR domain is required for inflammatory signalling in response to flagellin

Cited by 31 publications

References 15 publications

Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Tyrosine Phosphorylation of MyD88 Adapter-like (Mal) Is Critical for Signal Transduction and Blocked in Endotoxin Tolerance

Protein Kinase D Interaction with TLR5 Is Required for Inflammatory Signaling in Response to Bacterial Flagellin

HPV16E7d Candidate Vaccine Modified Genes Expression in Tumor Environment: Flic as Adjuvant Changed TGF-B Gene Expression

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