Role of MyD88 in Phosphatidylinositol 3-Kinase Activation by Flagellin/Toll-like Receptor 5 Engagement in Colonic Epithelial Cells
Open accessAbstract
Bacterial flagellin, recognized by Toll-like receptor (TLR) 5, is suggested to be involved in colonic inflammation. However, the detailed signaling mechanisms mediated by flagellin/TLR5 engagement are not clear. Here we dissected the biochemical mechanism by which TLR5 engagement mediates phosphatidylinositol 3-kinase (PI3K) activation in colonic epithelial cells. We demonstrate that silencing TLR5 expression in nontransformed human colonic epithelial cells blocks flagellin-induced PI3K activation, indicating specific activation of PI3K by flagellin/TLR5 engagement. Moreover, we determine that TLR5 recruits the p85 regulatory subunit of PI3K to its cytoplasmic TIR domain in response to flagellin. However, the Src homology binding "YXXM" motif in the cytoplasmic TIR domain of TLR5 is not involved in p85 recruitment, implying that TLR5 indirectly recruits p85. Indeed, we demonstrate that the adaptor molecule MyD88 associates with TLR5 and silencing MyD88 expression blocks PI3K activation by disrupting the association between TLR5 and p85. Furthermore, we show that MyD88 associates with p85 in response to flagellin. Additionally, we determine that blocking PI3K activation reduces interleukin-8 production induced by flagellin in human colonic epithelial cells. Together, MyD88 bridges TLR5 engagement to PI3K activation in response to flagellin.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
Signals that originate from luminal micro-organisms and influence the gut epithelium involve well-characterized mechanisms, such as Toll-like receptor signaling and signaling by bipeptides or tripeptides.
“Signals that originate from luminal micro-organisms and influence the gut epithelium have been studied extensively, and involve well-characterized mechanisms, such as Toll-like receptor signaling48,49 and signaling by bipeptides or tripeptides, such as N-formylmethionyl–leucyl–phenylalanine.50”
From Principles and clinical implications of the brain-gut-enteric microbiota axis (2009) · cites this paper as [49]
Cites
Akt Promotes Cell Survival by Phosphorylating and Inhibiting a Forkhead Transcription Factor
Brunet, A., Bonni, A., Zigmond, M. J., Lin, M. Z., Juo, P., Hu, L. S., Anderson, M. J., Arden, K. C., Blenis, J., & Greenberg, M. E. (1999) · Cell · doi:10.1016/s0092-8674(00)80595-4 · Cited by 6,535 · see citing works
The phosphoinositide 3-kinase pathway
Cantley, L. C. (2002) · Science · doi:10.1126/science.296.5573.1655 · Cited by 5,621 · see citing works
The two NF-κB activation pathways and their role in innate and adaptive immunity
Bonizzi, G., & Karin, M. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.03.008 · Cited by 2,535 · see citing works
Molecular Analysis of Commensal Host-Microbial Relationships in the Intestine
Hooper, L. V., Wong, M. H., Thelin, A., Hansson, L., Falk, P. G., & Gordon, J. I. (2001) · Science · doi:10.1126/science.291.5505.881 · Cited by 2,202 · see citing works
Oshiumi, H., Matsumoto, M., Funami, K., Akazawa, T., & Seya, T. (2003) · Nature Immunology · doi:10.1038/ni886 · Cited by 1,208 · see citing works
Katso, R., Okkenhaug, K., Ahmadi, K., White, S., Timms, J. F., & Waterfield, M. D. (2001) · Annual Review of Cell and Developmental Biology · doi:10.1146/annurev.cellbio.17.1.615 · Cited by 1,204 · see citing works
Smythies, L. E., Sellers, M. T., Clements, R. H., Mosteller‐Barnum, M., Meng, G., Benjamin, W. H., Orenstein, J. M., & Smith, P. D. (2005) · Journal of Clinical Investigation · doi:10.1172/jci200519229 · Cited by 924 · see citing works
Toll-like receptor 2–mediated NF-κB activation requires a Rac1-dependent pathway
Arbibe, L., Mira, J. P., Teusch, N. E., Kline, L., Guha, M., Mackman, N., Godowski, P. J., Ulevitch, R. J., & Knaus, U. G. (2000) · Nature Immunology · doi:10.1038/82797 · Cited by 664 · see citing works
PI3K and negative regulation of TLR signaling
Fukao, T., & Koyasu, S. (2003) · Trends in Immunology · doi:10.1016/s1471-4906(03)00139-x · Cited by 612 · see citing works
Akira, S. (2003) · Current Opinion in Immunology · doi:10.1016/s0952-7915(02)00013-4 · Cited by 585 · see citing works
Novel roles of TLR3 tyrosine phosphorylation and PI3 kinase in double-stranded RNA signaling
Sarkar, S. N., Peters, K. L., Elco, C. P., Sakamoto, S., Pal, S., & Sen, G. C. (2004) · Nature Structural & Molecular Biology · doi:10.1038/nsmb847 · Cited by 348 · see citing works
Ojaniemi, M., Glumoff, V., Harju, K., Vähä-Mäkilä, M., Vuori, K., & Hallman, M. (2003) · European Journal of Immunology · doi:10.1002/eji.200323376 · Cited by 321 · see citing works
Wennström, S., & Downward, J. (1999) · Molecular and Cellular Biology · doi:10.1128/mcb.19.6.4279 · Cited by 279 · see citing works
Rhee, S. H., & Hwang, D. H. (2000) · Journal of Biological Chemistry · doi:10.1074/jbc.m007386200 · Cited by 247 · see citing works
Self-citationPhosphatidylinositol 3-Kinase in Interleukin 1 Signaling
Reddy, S. A. G., Huang, J. H., & Liao, W. S. ‐. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.46.29167 · Cited by 230 · see citing works
Rhee, S. H., Im, E., Riegler, M., Kokkotou, E., O'Brien, M., & Pothoulakis, C. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0502174102 · Cited by 229 · see citing works
Self-citationMcGlade, C. J., Ellis, C. A., Reedijk, M., et al. (1992) · Molecular and Cellular Biology · doi:10.1128/mcb.12.3.991-997.1992 · Cited by 185 · see citing works
Phosphatidylinositol 3-kinase mediates proliferative signals in intestinal epithelial cells
Sheng, H., Shao, J., Townsend, C. M., & Evers, B. M. (2003) · Gut · doi:10.1136/gut.52.10.1472 · Cited by 144 · see citing works
TLRs: Professor Mechnikov, sit on your hat
O'Neill, L. A. J. (2004) · Trends in Immunology · doi:10.1016/j.it.2004.10.005 · Cited by 140 · see citing works
Sakaue, H., Ogawa, W., Takata, M., Kuroda, S., Kotani, K., Matsumoto, M., Sakaue, M., Nishio, S., Ueno, H., & Kasuga, M. (1997) · Molecular Endocrinology · doi:10.1210/mend.11.10.9986 · Cited by 125 · see citing works
Rhee, S. H., Jones, B. W., Toshchakov, V. Y., Vogel, S. N., & Fenton, M. J. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m208633200 · Cited by 115 · see citing works
Self-citationAksoy, E., Berghe, W. V., Detienne, S., Amraoui, Z., Fitzgerald, K. A., Haegeman, G., Goldman, M., & Willems, F. (2005) · European Journal of Immunology · doi:10.1002/eji.200425801 · Cited by 114 · see citing works
Rhee, S. H., Keates, A. C., Moyer, M. P., & Pothoulakis, C. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m400967200 · Cited by 81 · see citing works
Self-citationFerrand, A., Bertrand, C., Portolan, G., Cui, G., Carlson, J. E., Pradayrol, L., Fourmy, D., Dufresne, M., Wang, T. C., & Seva, C. (2005) · Cancer Research · doi:10.1158/0008-5472.can-04-0978 · Cited by 56 · see citing works
Wu, H., Windmiller, D. A., Wang, L., et al. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.c300225200 · Cited by 37 · see citing works
The yin and yang of intestinal differentiation: Key roles for lipid signaling
Barrett, K. E. (2001) · Gastroenterology · doi:10.1053/gast.2001.24395 · Cited by 1 · see citing works
Flagged first, then by citations
Cited by
Sorted by citations
Principles and clinical implications of the brain-gut-enteric microbiota axis
Rhee, S. H., Pothoulakis, C., & Mayer, E. A. (2009) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2009.35 · Cited by 1,342 · see citing works
“Microbe–gut–brain signaling Signals that originate from luminal micro-organisms and influence the gut epithelium have been studied extensively, and involve well-characterized mechanisms, such as Toll-like receptor signalin”
Self-citationPokusaeva, K., Johnson, C., Luk, B., Uribe, G., Fu, Y., Oezguen, N., Matsunami, R. K., Lugo, M., Major, A., Mori‐Akiyama, Y., et al. (2017) · Neurogastroenterology & Motility · doi:10.1111/nmo.12904 · Cited by 337 · see citing works
Zhao, S., Dejanovic, D., Yao, P., Bhilocha, S., Sadler, T., Schirbel, A., West, G., Doyon, G., Lopez, R., Mao, R., et al. (2020) · Mucosal Immunology · doi:10.1038/s41385-020-0259-9 · Cited by 59 · see citing works
Uchida, M., Oyanagi, E., Kawanishi, N., Iemitsu, M., Miyachi, M., Kremenik, M. J., Onodera, S., & Yano, H. (2014) · Immunology Letters · doi:10.1016/j.imlet.2013.12.021 · Cited by 18 · see citing works
- Authors
- Rhee, S. H., Kim, H., Moyer, M. P., & Pothoulakis, C.
- Affiliations
- Beth Israel Deaconess Medical Center (US)
- Incell Corporation (United States) (US)
- Corresponding author
- Pothoulakis, Charalabos
- Venue
- Journal of Biological Chemistry
- Publisher
- Elsevier BV
- Published
- 2006-07
- Volume
- 281
- Issue
- 27
- Pages
- 18560-18568
- ISSN
- 0021-9258 (ISSN-L)
- OpenAlex
- W2089360911
- Cited by
- 103
- References
- 26
- Citations by year
- 2026: 1 · 2025: 3 · 2024: 4 · 2023: 2 · 2022: 3 · 2021: 2 · 2020: 8 · 2019: 4 · 2018: 2 · 2017: 5 · 2016: 2 · 2015: 4 · 2014: 7 · 2013: 9 · 2012: 7
- FWCI
- 3.66
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Journal of Biological Chemistry (publishedVersion, cc-by)
- PubMed (publishedVersion)
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › Immune Response and Inflammation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › NF-κB Signaling Pathways
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Inflammasome and immune disorders
- Keywords
- MyD88, TLR5, flagellin, p85 regulatory subunit, colonic epithelial cells, TIR domain, colonic inflammation, bacterial flagellin
- MeSH terms
- Animals, Cell Line, Colon, Enzyme Activation, Epithelial Cells, Flagellin, Humans, Male, Mice, Inbred C3H, Protein Binding, Signal Transduction, Interleukin-8, Phosphatidylinositol 3-Kinases, Adaptor Proteins, Signal Transducing, Toll-Like Receptor 5, Mice, Myeloid Differentiation Factor 88
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
