Luminal trypsin may regulate enterocytes through proteinase-activated receptor 2
Open accessAbstract
Proteinase-activated receptor 2 (PAR-2) is a recently characterized G-protein coupled receptor that is cleaved and activated by pancreatic trypsin. Trypsin is usually considered a digestive enzyme in the intestinal lumen. We examined the hypothesis that trypsin, at concentrations normally present in the lumen of the small intestine, is also a signaling molecule that specifically regulates enterocytes by activating PAR-2. PAR-2 mRNA was highly expressed in the mucosa of the small intestine and in an enterocyte cell line. Immunoreactive PAR-2 was detected at the apical membrane of enterocytes, where it could be cleaved by luminal trypsin. Physiological concentrations of pancreatic trypsin and a peptide corresponding to the tethered ligand of PAR-2, which is exposed by trypsin cleavage, stimulated generation of inositol 1,4,5-trisphosphate, arachidonic acid release, and secretion of prostaglandin E 2 and F 1α from enterocytes and a transfected cell line. Application of trypsin to the apical membrane of enterocytes and to the mucosal surface of everted sacs of jejunum also stimulated prostaglandin E 2 secretion. Thus, luminal trypsin activates PAR-2 at the apical membrane of enterocytes to stimulate secretion of eicosanoids, which regulate multiple cell types in a paracrine and autocrine manner. We conclude that trypsin is a signaling molecule that specifically regulates enterocytes by triggering PAR-2.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Apical administration of PAR-2 activating ligands led to prostanoid and interferon release as well as an increase in paracellular permeability due to ZO-1 degradation.
“Regarding the role of PARs in intestinal function, apical administration of PAR-2 activating ligands led to prostanoid and interferon release as well as an increase in paracellular permeability due to ZO-1 degradation.6,134”
From The emerging roles of bacterial proteases in intestinal diseases (2023) · cites this paper as [6]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Vu, T.-K. H., Hung, D. T., Wheaton, V. I., & Coughlin, S. R. (1991) · Cell · doi:10.1016/0092-8674(91)90261-v · Cited by 2,967 · see citing works
cPLA2 is phosphorylated and activated by MAP kinase
Lin, L., Wartmann, M., Lin, A. Y., Knopf, J. L., Seth, A., & Davis, R. J. (1993) · Cell · doi:10.1016/0092-8674(93)90666-e · Cited by 1,851 · see citing works
Clark, J. D., Lin, L.-L., Kriz, R. W., Ramesha, C. S., Sultzman, L. A., Lin, A. Y., Milona, N., & Knopf, J. L. (1991) · Cell · doi:10.1016/0092-8674(91)90556-e · Cited by 1,688 · see citing works
Physiology of the Gastrointestinal Tract
Ouyang, A. (1988) · JAMA · doi:10.1001/jama.1988.03410100162049 · Cited by 969 · see citing works
Molecular cloning of a potential proteinase activated receptor.
Nystedt, S., Emilsson, K., Wahlestedt, C., & Sundelin, J. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.20.9208 · Cited by 887 · see citing works
Protease-activated receptor 3 is a second thrombin receptor in humans
Ishihara, H., Connolly, A. J., Zeng, D., Kahn, M. L., Zheng, Y. W., Timmons, C., Tram, T., & Coughlin, S. R. (1997) · Nature · doi:10.1038/386502a0 · Cited by 865 · see citing works
Weksler, B. B., Ley, C. W., & JAFFE, E. A. (1978) · Journal of Clinical Investigation · doi:10.1172/jci109220 · Cited by 719 · see citing works
Interactions of Mast Cell Tryptase with Thrombin Receptors and PAR-2
Molino, M., Barnathan, E. S., Numerof, R. P., Clark, J., Dreyer, M. L., Cumashi, A., Hoxie, J. A., Schechter, N. M., Woolkalís, M. J., & Brass, L. F. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.7.4043 · Cited by 591 · see citing works
Molecular cloning, expression and potential functions of the human proteinase-activated receptor-2
Böhm, S. K., Kong, W., Brömme, D., Smeekens, S. P., ANDERSON, D. C., Connolly, A. J., Kahn, M. L., Nelken, N. A., Coughlin, S. R., Payan, D. G., et al. (1996) · Biochemical Journal · doi:10.1042/bj3141009 · Cited by 459 · see citing works
Self-citationEicosanoids and the gastrointestinal tract
Eberhart, C. E., & DuBois, R. N. (1995) · Gastroenterology · doi:10.1016/0016-5085(95)90296-1 · Cited by 415 · see citing works
Bills, T. K., Smith, J. B., & Silver, M. J. (1977) · Journal of Clinical Investigation · doi:10.1172/jci108745 · Cited by 409 · see citing works
The Proteinase-activated Receptor 2 Is Induced by Inflammatory Mediators in Human Endothelial Cells
Nystedt, S., Ramakrishnan, V., & Sundelin, J. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.25.14910 · Cited by 356 · see citing works
Cellular consequences of thrombin-receptor activation
Grand, R. J. A., Turnell, A. S., & Grabham, P. W. (1996) · Biochemical Journal · doi:10.1042/bj3130353 · Cited by 333 · see citing works
Mechanisms of Desensitization and Resensitization of Proteinase-activated Receptor-2
Bühm, S. K., Khitin, L. M., Grady, E. F., Aponte, G. W., Payan, D. G., & Bunnett, N. W. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.36.22003 · Cited by 250 · see citing works
Self-citationParker, J., Daniel, L. W., & Waite, M. (1987) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(18)61199-8 · Cited by 230 · see citing works
Ligand Cross-reactivity within the Protease-activated Receptor Family
Blackhart, B. D., Emilsson, K., Nguyen, D., et al. (1996) · Journal of Biological Chemistry · doi:10.1074/jbc.271.28.16466 · Cited by 214 · see citing works
Saifeddine, M., Al‐Ani, B., Cheng, C., Wang, L., & Hollenberg, M. D. (1996) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.1996.tb15433.x · Cited by 198 · see citing works
Self-citationKramer, R. M., Roberts, E. F., Manetta, J. V., et al. (1993) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(19)74383-x · Cited by 189 · see citing works
Santulli, R. J., Derian, C. K., Darrow, A. L., Tomko, K. A., Eckardt, A. J., Seiberg, M., Scarborough, R. M., & Andrade‐Gordon, P. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.20.9151 · Cited by 183 · see citing works
Bártoli, F., Lin, H. K., Ghomashchi, F., Gelb, M. H., Jain, M. K., & Apitz-Castro, R. J. (1994) · Journal of Biological Chemistry · doi:10.1016/s0021-9258(17)40727-7 · Cited by 182 · see citing works
Garland, A. M., Grady, E. F., Lovett, M., Vigna, S. R., Frucht, M. M., Krause, J. E., & Bunnett, N. W. (1996) · Molecular Pharmacology · doi:10.1016/s0026-895x(25)08730-9 · Cited by 157 · see citing works
Self-citationKramer, R. M., Roberts, E. F., Hyslop, P. A., et al. (1995) · Journal of Biological Chemistry · doi:10.1074/jbc.270.24.14816 · Cited by 126 · see citing works
Effect of partial exclusion of pancreatic juice on rat basal pancreatic secretion
Miyasaka, K., & Green, G. M. (1984) · Gastroenterology · doi:10.1016/0016-5085(84)90596-1 · Cited by 108 · see citing works
Hwa, J. J., Ghibaudi, L., Williams, P., Chintala, M. S., Zhang, R., Chatterjee, M., & Sybertz, E. J. (1996) · Circulation Research · doi:10.1161/01.res.78.4.581 · Cited by 108 · see citing works
Importance of bile in regulation of intraluminal proteolytic enzyme activities in the rat
Green, G. M., & Nasset, E. S. (1980) · Gastroenterology · doi:10.1016/0016-5085(80)90247-4 · Cited by 99 · see citing works
Endocytosis and recycling of neurokinin 1 receptors in enteric neurons
Grady, E. F., Gamp, P. D., Jones, E. F., Bałuk, P., McDonald, D. M., Payan, D. G., & Bunnett, N. W. (1996) · Neuroscience · doi:10.1016/0306-4522(96)00357-0 · Cited by 81 · see citing works
Self-citationMari, B. P., Guérin, S., Far, D. F., et al. (1996) · The FASEB Journal · doi:10.1096/fasebj.10.2.8641564 · Cited by 77 · see citing works
Coller, B. S., Ward, P. E., Ceruso, M., et al. (1992) · Biochemistry · doi:10.1021/bi00162a007 · Cited by 61 · see citing works
Taniguchi, M., Kashiwayanagi, M., & Kurihara, K. (1996) · Journal of Neuroscience · doi:10.1523/jneurosci.16-03-01239.1996 · Cited by 41 · see citing works
Aponte, G. W., Keddie, B. A., Halldén, G., et al. (1991) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.88.12.5282 · Cited by 16 · see citing works
α-thrombin and trypsin use different receptors to stimulate arachidonic acid metabolism
Levine, L. (1994) · Prostaglandins · doi:10.1016/0090-6980(94)90044-2 · Cited by 9 · see citing works
Flagged first, then by citations
Research works printed but not linked: 4
- [1]Nystedt, S., Emilsson, K., Wahlestedt, C. & Sundelin, J. (1994) Proc. Natl. Acad. Sci. USA 91, 9208-9212.
- [7]Santulli, R. J., Derian, C. K., Darrow, A. L., Tomko, K. A., Eckardt, A. J., Seiberg, M., Scarborough, R. M. & AndradeGordon, P. (1995) Proc. Natl. Acad. Sci. USA 92, 9151-9155.
- [20]Aponte, G. W., Keddie, A., Hallden, G., Hess, R. & Link, P. (1991) Proc. Natl. Acad. Sci. USA 88, 5282-5286.
- [28]Coller, B. S., Ward, P., Ceruso, M., Scudder, L. E., Springer, K., Kutok, J. & Prestwich, G. D. (1992) Biochemistry 31, 1171311720.
Cited by
Sorted by citations
Electrolyte transport in the mammalian colon: mechanisms and implications for disease
Kunzelmann, K., & Mall, M. (2002) · Physiological Reviews · doi:10.1152/physrev.00026.2001 · Cited by 655 · see citing works
Sturgeon, C., & Fasano, A. (2016) · Tissue Barriers · doi:10.1080/21688370.2016.1251384 · Cited by 497 · see citing works
Protease-activated receptors in inflammation, neuronal signaling and pain
Vergnolle, N., Wallace, J. L., Bunnett, N. W., & Hollenberg, M. D. (2001) · Trends in Pharmacological Sciences · doi:10.1016/s0165-6147(00)01634-5 · Cited by 369 · see citing works
Self-citationStructure, function and pathophysiology of protease activated receptors
Adams, M. N., Ramachandran, R., Yau, M.-K., Suen, J. Y., Fairlie, D. P., Hollenberg, M. D., & Hooper, J. D. (2011) · Pharmacology & Therapeutics · doi:10.1016/j.pharmthera.2011.01.003 · Cited by 370 · see citing works
Self-citationMast Cell Tryptase Controls Paracellular Permeability of the Intestine
Jacob, C., Yang, P.-C., Darmoul, D., Amadesi, S., Saito, T., Cottrell, G. S., Coelho, A.-M., Singh, P., Grady, E. F., Perdue, M., et al. (2005) · Journal of Biological Chemistry · doi:10.1074/jbc.m506338200 · Cited by 334 · see citing works
Self-citationGecse, K., Róka, R., Ferrier, L., Leveque, M., Eutamene, H., Cartier, C., Ait-Belgnaoui, A., Rosztóczy, A., Izbéki, F., Fioramonti, J., et al. (2008) · Gut · doi:10.1136/gut.2007.140210 · Cited by 314 · see citing works
Reed, D. E., Barajas‐Lopez, C., Cottrell, G., Velazquez‐Rocha, S., Dery, O., Grady, E. F., Bunnett, N. W., & Vanner, S. J. (2003) · The Journal of Physiology · doi:10.1113/jphysiol.2002.032011 · Cited by 192 · see citing works
Self-citationLourbakos, A., Chinni, C., Thompson, P., Potempa, J., Travis, J., Mackie, E. J., & Pike, R. N. (1998) · FEBS Letters · doi:10.1016/s0014-5793(98)01036-9 · Cited by 171 · see citing works
The protease-activated receptor-2 upregulates keratinocyte phagocytosis
Sharlow, E. R., Paine, C. S., Babiarz, L., Eisinger, M., Shapiro, S., & Seiberg, M. (2000) · Journal of Cell Science · doi:10.1242/jcs.113.17.3093 · Cited by 150 · see citing works
Cenac, N., Chin, A. C., Garcia‐Villar, R., Salvador‐Cartier, C., Ferrier, L., Vergnolle, N., Buret, A. G., Fioramonti, J., & Bueno, L. (2004) · The Journal of Physiology · doi:10.1113/jphysiol.2004.061721 · Cited by 140 · see citing works
Cenac, N., Garcia-Villar, R., Ferrier, L., Larauche, M., Vergnolle, N., Bunnett, N. W., Coelho, A.-M., Fioramonti, J., & Bueno, L. (2003) · The Journal of Immunology · doi:10.4049/jimmunol.170.8.4296 · Cited by 139 · see citing works
Self-citationDulon, S., Leduc, D., Cottrell, G. S., D'Alayer, J., Hansen, K. K., Bunnett, N. W., Hollenberg, M. D., Pidard, D., & Chignard, M. (2005) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2004-0274oc · Cited by 139 · see citing works
Self-citationProtease-activated receptors in health and disease
Peach, C. J., Edgington-Mitchell, L. E., Bunnett, N. W., & Schmidt, B. L. (2023) · Physiological Reviews · doi:10.1152/physrev.00044.2021 · Cited by 116 · see citing works
Self-citationScott, G., Rodriguez-Burford, C., Seiberg, M., Han, R., Babiarz, L., Grizzle, W., Bell, W., Pentland, A., & Deng, A. (2001) · Journal of Investigative Dermatology · doi:10.1046/j.0022-202x.2001.01575.x · Cited by 110 · see citing works
The bidirectional communication between neurons and mast cells within the gastrointestinal tract
Van Nassauw, L., Adriaensen, D., & Timmermans, J.-P. (2007) · Autonomic Neuroscience · doi:10.1016/j.autneu.2006.10.003 · Cited by 99 · see citing works
The emerging roles of bacterial proteases in intestinal diseases
Caminero, A., Guzman, M., Libertucci, J., & Lomax, A. E. (2023) · Gut Microbes · doi:10.1080/19490976.2023.2181922 · Cited by 92 · see citing works
Kim, H. S., Lim, J. H., Park, H., & Lee, S. I. (2010) · Yonsei Medical Journal · doi:10.3349/ymj.2010.51.1.45 · Cited by 85 · see citing works
Cottrell, G. S., Amadesi, S., Pikios, S., Camerer, E., Willardsen, J. A., Murphy, B. R., Caughey, G. H., Wolters, P. J., Coughlin, S. R., Peterson, A., et al. (2007) · Gastroenterology · doi:10.1053/j.gastro.2007.03.101 · Cited by 56 · see citing works
Self-citationMadecassoside Inhibits Melanin Synthesis by Blocking Ultraviolet-Induced Inflammation
Jung, E., Lee, J.-A., Shin, S., Roh, K.-B., Kim, J.-H., & Park, D. (2013) · Molecules · doi:10.3390/molecules181215724 · Cited by 52 · see citing works
- Authors
- Kong, W., McConalogue, K., Khitin, L. M., Hollenberg, M. D., Payan, D. G., Böhm, S. K., & Bunnett, N. W.
- Affiliations
- University of Calgary (CA)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 1997-08-05
- Volume
- 94
- Issue
- 16
- Pages
- 8884-8889
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC23180
- OpenAlex
- W2012730541
- Cited by
- 318
- References
- 31
- Citations by year
- 2026: 5 · 2024: 3 · 2023: 3 · 2022: 9 · 2021: 3 · 2020: 4 · 2019: 6 · 2018: 4 · 2017: 3 · 2016: 8 · 2015: 8 · 2014: 8 · 2013: 8 · 2012: 10
- FWCI
- 9.03
- Type
- journal article
- Language
- en
- Open access
- green
- europepmc.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Topics
- Health Sciences › Medicine › Hematology › Blood Coagulation and Thrombosis Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Protease and Inhibitor Mechanisms
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
- Keywords
- protease-activated receptor 2, pancreatic trypsin, enterocytes, small intestine, G protein-coupled receptors, apical membrane, prostaglandin E2, prostaglandin F1alpha, inositol 1,4,5-trisphosphate, arachidonic acid release, paracrine signaling, autocrine signaling, jejunum
- MeSH terms
- Animals, Cell Line, Intestinal Mucosa, Intestine, Small, Prostaglandins, Receptors, Cell Surface, Trypsin, Signal Transduction, Receptor, PAR-2, Rats
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
