The DOI matches its Crossref record; 57 of the 57 references it cites were found in a registry or an index.
Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis
Open accessAbstract
Epithelial barrier loss is a driver of intestinal and systemic diseases. Myosin light chain kinase (MLCK) is a key effector of barrier dysfunction and a potential therapeutic target, but enzymatic inhibition has unacceptable toxicity. Here, we show that a unique domain within the MLCK splice variant MLCK1 directs perijunctional actomyosin ring (PAMR) recruitment. Using the domain structure and multiple screens, we identify a domain-binding small molecule (divertin) that blocks MLCK1 recruitment without inhibiting enzymatic function. Divertin blocks acute, tumor necrosis factor (TNF)-induced MLCK1 recruitment as well as downstream myosin light chain (MLC) phosphorylation, barrier loss, and diarrhea in vitro and in vivo. Divertin corrects barrier dysfunction and prevents disease development and progression in experimental inflammatory bowel disease. Beyond applications of divertin in gastrointestinal disease, this general approach to enzymatic inhibition by preventing access to specific subcellular sites provides a new paradigm for safely and precisely targeting individual properties of enzymes with multiple functions.
Overview
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
Verification
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?
In the citing paper
“Importantly, they provided the evidence that treatment with divertin regulate paracellular transport rather than transcellular transport across the membranes.”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
In the citing paper
“Further, they showed that treatment with divertin blocked acute interferon gamma–primed TNF-induced MLC phosphorylation and barrier loss in Caco-2 monolayers model system.”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
In the citing paper
“Treatment with divertin also reduced the progression and severity of experimental chronic colitis of T cell transfer model (CD4+ effector T cells in immunodeficient mice) by correcting gut permeability.191”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
In the citing paper
“Further, they demonstrated that treatment with divertin corrected increased intestinal permeability in IL-10–/– mice (spontaneous colitis model) without significant systemic, mucosal, or epithelial toxicity.191”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
In the citing paper
“It was shown by the Turner group that a domain binding small molecule called “divertin” blocks the recruitment of MLCK1 without inhibiting enzyme function.191”
From Regulation of Intestinal Barrier Function by Microbial Metabolites (2021) · cites this paper as [191]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
Coot : model-building tools for molecular graphics
Emsley, P., & Cowtan, K. (2004) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444904019158 · Cited by 30,571
Overview of the CCP 4 suite and current developments
Winn, M. D., Ballard, C. C., Cowtan, K. D., Dodson, E. J., Emsley, P., Evans, P. R., Keegan, R. M., Krissinel, E. B., Leslie, A. G. W., McCoy, A., et al. (2011) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444910045749 · Cited by 12,353
Interleukin-10-deficient mice develop chronic enterocolitis
Kühn, R., Löhler, J., Rennick, D. M., Rajewsky, K., & Müller, W. (1993) · Cell · doi:10.1016/0092-8674(93)80068-p · Cited by 4,248
ZINC − A Free Database of Commercially Available Compounds for Virtual Screening
Irwin, J. J., & Shoichet, B. K. (2005) · Journal of Chemical Information and Modeling · doi:10.1021/ci049714+ · Cited by 4,058
Intestinal mucosal barrier function in health and disease
Turner, J. R. (2009) · Nature reviews. Immunology · doi:10.1038/nri2653 · Cited by 3,952
Self-citationThe Immunoglobulin Superfamily: Domains For Cell Surface Recognition
Williams, A., & Barclay, A. N. (1988) · Annual Review of Immunology · doi:10.1146/annurev.iy.06.040188.002121 · Cited by 2,270
A chemical method for fast and sensitive detection of DNA synthesis in vivo
Salic, A. N., & Mitchison, T. J. (2008) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0712168105 · Cited by 1,859
Kebir, H., Kreymborg, K., Ifergan, I., Dodelet-Devillers, A., Cayrol, R., Bernard, M., Giuliani, F., Arbour, N., Becher, B., & Prat, A. (2007) · Nature Medicine · doi:10.1038/nm1651 · Cited by 1,759
The intestinal epithelial barrier: a therapeutic target?
Odenwald, M. A., & Turner, J. R. (2017) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/nrgastro.2016.169 · Cited by 1,288
Self-citationPowrie, F., Leach, M. W., Mauze, S., Menon, S., Barcomb Caddle, L., & Coffman, R. L. (1994) · Immunity · doi:10.1016/1074-7613(94)90045-0 · Cited by 1,146
Berg, D., Davidson, N. M., Kühn, R., Müller, W., Menon, S., Holland, G., Thompson-Snipes, L., Leach, M. W., & Rennick, D. M. (1996) · Journal of Clinical Investigation · doi:10.1172/jci118861 · Cited by 1,125
Wang, F., Graham, W. V., Wang, Y., Witkowski, E. D., Schwarz, B. T., & Turner, J. R. (2005) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)62264-x · Cited by 692
Self-citationIntestinal permeability and the prediction of relapse in Crohn's disease
Wyatt, J., Vogelsang, H., Hübl, W., Waldhoer, T., & Lochs, H. (1993) · The Lancet · doi:10.1016/0140-6736(93)90882-h · Cited by 626
Dedicated Myosin Light Chain Kinases with Diverse Cellular Functions
Kamm, K. E., & Stull, J. T. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.r000028200 · Cited by 574
Overview of the CCP4 suite and current developments.
Winn, M. D., Ballard, C. C., Cowtan, K. D., et al. (2011) · Apollo (University of Cambridge) · doi:10.17863/cam.52322 · Cited by 564
Turner, J. R., Rill, B. K., Carlson, S. L., Carnes, D., Kerner, R., Mrsny, R. J., & Madara, J. (1997) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.1997.273.4.c1378 · Cited by 553
Self-citationMarchiando, A. M., Shen, L., Graham, W. V., Weber, C. R., Schwarz, B. T., Austin, J. R., Raleigh, D. R., Guan, Y., Watson, A. J. M., Montrose, M. H., et al. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200902153 · Cited by 475
Self-citationSu, L., Shen, L., Clayburgh, D. R., Nalle, S. C., Sullivan, E. A., Meddings, J. B., Abraham, C., & Turner, J. R. (2009) · Gastroenterology · doi:10.1053/j.gastro.2008.10.081 · Cited by 455
Self-citationClayburgh, D. R. (2005) · Journal of Clinical Investigation · doi:10.1172/jci24970 · Cited by 419
Su, L., Nalle, S. C., Shen, L., Turner, E. S., Singh, G., Breskin, L. A., Khramtsova, E. A., Khramtsova, G. F., Tsai, P., Fu, Y., et al. (2013) · Gastroenterology · doi:10.1053/j.gastro.2013.04.011 · Cited by 393
Self-citationZolotarevsky, Y., Hecht, G. A., Koutsouris, A., Gonzalez, D. E., Quan, C., Tom, J., Mrsny, R. J., & Turner, J. R. (2002) · Gastroenterology · doi:10.1053/gast.2002.34235 · Cited by 385
Self-citationBühner, S., Büning, C., Genschel, J., Kling, K., Herrmann, D., Dignass, A., Kuechler, I., Krueger, S., Schmidt, H. H.-J., & Lochs, H. (2005) · Gut · doi:10.1136/gut.2005.065557 · Cited by 381
Intestinal Permeability Defects: Is It Time to Treat?
Odenwald, M. A., & Turner, J. R. (2013) · Clinical Gastroenterology and Hepatology · doi:10.1016/j.cgh.2013.07.001 · Cited by 366
Self-citationReducing small intestinal permeability attenuates colitis in the IL10 gene-deficient mouse
Arrieta, M., Madsen, K. L., Doyle, J. S. G., & Meddings, J. B. (2008) · Gut · doi:10.1136/gut.2008.150888 · Cited by 324
Wang, F., Schwarz, B. T., Graham, W. V., Wang, Y., Su, L., Clayburgh, D. R., Abraham, C., & Turner, J. R. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.08.022 · Cited by 305
Self-citationBennett, J. L., Basivireddy, J., Kollar, A., Biron, K. E., Reickmann, P., Jefferies, W. A., & McQuaid, S. (2010) · Journal of Neuroimmunology · doi:10.1016/j.jneuroim.2010.08.011 · Cited by 271
Vetrano, S., Rescigno, M., Cera, M. R., Correale, C., Rumio, C., Doni, A., Fantini, M. C., Sturm, A., Borroni, E. M., Repici, A., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.04.002 · Cited by 254
PtdIns(3)P controls cytokinesis through KIF13A-mediated recruitment of FYVE-CENT to the midbody
Sagona, A. P., Nezis, I. P., Pedersen, N. M., Liestøl, K., Poulton, J., Rusten, T. E., Skotheim, R. I., Raiborg, C., & Stenmark, H. (2010) · Nature Cell Biology · doi:10.1038/ncb2036 · Cited by 239
Intestinal permeability in children with Crohn's disease and coeliac disease.
Pearson, A., EASTHAM, E. J., Laker, M. F., Craft, A. W., & NELSON, R. L. (1982) · BMJ · doi:10.1136/bmj.285.6334.20 · Cited by 225
Clayburgh, D. R., Musch, M. W., Leitges, M., Fu, Y., & Turner, J. R. (2006) · Journal of Clinical Investigation · doi:10.1172/jci29218 · Cited by 203
Self-citationBuschmann, M. M., Shen, L., Rajapakse, H., Raleigh, D. R., Wang, Y., Wang, Y., Lingaraju, A., Zha, J., Abbott, E., McAuley, E. M., et al. (2013) · Molecular Biology of the Cell · doi:10.1091/mbc.e12-09-0688 · Cited by 192
Self-citationHe, W., Peng, Y., Zhang, W., Lv, N., Tang, J. P., Chen, C., Zhang, C., Gao, S., Chen, H., Zhi, G., et al. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.05.032 · Cited by 184
Self-citationClayburgh, D. R., Rosen, S., Witkowski, E. D., Wang, F., Blair, S. A., Dudek, S. M., Garcia, J. G. N., Alverdy, J. C., & Turner, J. R. (2004) · Journal of Biological Chemistry · doi:10.1074/jbc.m408822200 · Cited by 180
Self-citationConditional Peripheral Membrane Proteins: Facing up to Limited Specificity
Moravcevic, K., Oxley, C. L., & Lemmon, M. A. (2011) · Structure · doi:10.1016/j.str.2011.11.012 · Cited by 173
Automated search-model discovery and preparation for structure solution by molecular replacement
Keegan, R. M., & Winn, M. (2007) · Acta Crystallographica Section D Biological Crystallography · doi:10.1107/s0907444907002661 · Cited by 167
Wapenaar, M. C., Monsuur, A. J., Bodegraven, A. A. V., Weersma, R., Bevova, M. R., Linskens, R. K., Howdle, P. D., Holmes, G. K. T., Mulder, C. J. J., Dijkstra, G. D. H., et al. (2007) · Gut · doi:10.1136/gut.2007.133132 · Cited by 163
Diverse Regulation of Claudin-1 and Claudin-4 in Atopic Dermatitis
Gruber, R. W., Börnchen, C., Rose, K., Daubmann, A., Volksdorf, T., Wladykowski, E., Vidal‐y‐Sy, S., Peters, E. M. J., Danso, M. O., Bouwstra, J. A., et al. (2015) · American Journal Of Pathology · doi:10.1016/j.ajpath.2015.06.021 · Cited by 155
Birukov, K. G., Csoŕtos, C., Marzilli, L. A., Dudek, S. M., Ma, S., Bresnick, A. R., Verin, A. D., Cotter, R. J., & Garcia, J. (2001) · Journal of Biological Chemistry · doi:10.1074/jbc.m005270200 · Cited by 151
Graham, W. V., Wang, F., Clayburgh, D. R., Cheng, J. X., Yoon, B., Wang, Y., Lin, A., & Turner, J. R. (2006) · Journal of Biological Chemistry · doi:10.1074/jbc.m602164200 · Cited by 146
Self-citationHolden, H. M., Ito, M., Hartshorne, D. J., & Rayment, I. (1992) · Journal of Molecular Biology · doi:10.1016/0022-2836(92)90226-a · Cited by 145
Wainwright, M. S., Rossi, J. L., Schavocky, J. P., Crawford, S. E., Steinhorn, D. M., Velentza, A. V., Zasadzki, M., Shirinsky, V. P., Jia, Y., Haiech, J., et al. (2003) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1031595100 · Cited by 141
A Single Human Myosin Light Chain Kinase Gene (MLCK; MYLK)Transcribes Multiple Nonmuscle Isoforms
Lazar, V., & Garcia, J. G. N. (1999) · Genomics · doi:10.1006/geno.1999.5774 · Cited by 136
Russo, J. M., Florian, P., Shen, L., Graham, W. V., Tretiakova, M., Gitter, A. H., Mrsny, R. J., & Turner, J. R. (2005) · Gastroenterology · doi:10.1053/j.gastro.2005.01.004 · Cited by 126
Self-citationXu, J., Gao, X.-P., Ramchandran, R., Zhao, Y., Vogel, S. M., & Malik, A. B. (2008) · Nature Immunology · doi:10.1038/ni.1628 · Cited by 113
Berglund, J. J., Riegler, M. F., Zolotarevsky, Y., Wenzl, E., & Turner, J. R. (2001) · American Journal of Physiology-Gastrointestinal and Liver Physiology · doi:10.1152/ajpgi.2001.281.6.g1487 · Cited by 102
Self-citationTumor necrosis factor inhibitor ameliorates murine intestinal graft-versus-host disease
Brown, G., Lindberg, G. M., Meddings, J. B., Silva, M., Beutler, B., & Thiele, D. L. (1999) · Gastroenterology · doi:10.1016/s0016-5085(99)70181-2 · Cited by 97
Turner, J. R., & Black, E. D. (2001) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2001.281.5.c1533 · Cited by 77
Self-citationMirzapoiazova, T., Moitra, J., Moreno‐Vinasco, L., Sammani, S., Turner, J. R., Chiang, E. T., Evenoski, C. L., Wang, T., Singleton, P. A., Huang, Y., et al. (2010) · American Journal of Respiratory Cell and Molecular Biology · doi:10.1165/rcmb.2009-0197oc · Cited by 77
Self-citation220- and 130-kDa MLCKs have distinct tissue distributions and intracellular localization patterns
Blue, E. K., Goeckeler, Z. M., Jin, Y., Hou, L., Dixon, S. A. H., Herring, B. P., Wysolmerski, R. B., & Gallagher, P. J. (2002) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.00333.2001 · Cited by 75
Myosin Light Chain Kinase Knockout
Somlyo, A. V., Wang, H., Choudhury, N., Khromov, A. S., Majesky, M. W., Owens, G. K., & Somlyo, A. P. (2004) · Journal of Muscle Research and Cell Motility · doi:10.1023/b:jure.0000038362.84697.c0 · Cited by 72
Agonist-induced isometric contraction of smooth muscle cell-populated collagen gel fiber
Oishi, K., Itoh, Y., Isshiki, Y., Kai, C., Takeda, Y., Yamaura, K., Takano‐Ohmuro, H., & Uchida, M. K. (2000) · American Journal of Physiology-Cell Physiology · doi:10.1152/ajpcell.2000.279.5.c1432 · Cited by 47
Blood pressure homeostasis is maintained by a P311–TGF-β axis
Badri, K. R., Yue, M., Carretero, O. A., Aramgam, S. L., Cao, J., Sharkady, S. M., Kim, G. H., Taylor, G. A., Byron, K. L., & Schuger, L. A. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69884 · Cited by 38
A Strategy to Identify Stable Membrane-Permeant Peptide Inhibitors of Myosin Light Chain Kinase
Owens, S. E., Graham, W. V., Siccardi, D., Turner, J. R., & Mrsny, R. J. (2005) · Pharmaceutical Research · doi:10.1007/s11095-005-2584-9 · Cited by 35
Self-citationWebb, B. A., White, K. A., Grillo‐Hill, B. K., Schönichen, A., Choi, C., & Barber, D. L. (2016) · Journal of Biological Chemistry · doi:10.1074/jbc.m116.736215 · Cited by 33
Lin, H., Cadete, V. J. J., Sawicka, J., Woźniak, M., & Sawicki, G. (2012) · Journal of Proteomics · doi:10.1016/j.jprot.2012.06.016 · Cited by 32
Prager, M., Durmus, T., Büttner, J., Molnár, T., de Jong, D. J., Drenth, J. P. H., Baumgart, D. C., Sturm, A., Farkas, K., Witt, H., et al. (2014) · Scandinavian Journal of Gastroenterology · doi:10.3109/00365521.2014.928903 · Cited by 19
The NCI Developmental Therapeutics Program.
Collins, J. M. (2006) · PubMed · Cited by 11
Cited by
Sorted by citations
Regulation of Intestinal Barrier Function by Microbial Metabolites
Ghosh, S., Whitley, C. S., Haribabu, B., & Jala, V. R. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.02.007 · Cited by 835
Paracellular permeability and tight junction regulation in gut health and disease
Horowitz, A., Chánez-Paredes, S. D., Haest, X., & Turner, J. R. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00766-3 · Cited by 748
Self-citationTight Junction Structure and Function Revisited
Otani, T., & Furuse, M. (2020) · Trends in Cell Biology · doi:10.1016/j.tcb.2020.08.004 · Cited by 669
The intestinal barrier: a pivotal role in health, inflammation, and cancer
Neurath, M. F., Artis, D., & Becker, C. (2025) · The Lancet. Gastroenterology & hepatology · doi:10.1016/s2468-1253(24)00390-x · Cited by 593
Gut barrier disruption and chronic disease
Martel, J., Chang, S.-H., Ko, Y.-F., Hwang, T.-L., Young, J. D., & Ojcius, D. M. (2022) · Trends in Endocrinology & Metabolism · doi:10.1016/j.tem.2022.01.002 · Cited by 514
Metadata
- Authors
- Graham, W. V., He, W., Marchiando, A. M., Zha, J., Singh, G., Li, H.-S., Biswas, A., Ong, M. L. D. M., Jiang, Z.-H., Choi, W., Zuccola, H., Wang, Y., Griffith, J., Wu, J., Rosenberg, H. J., Wang, Y., Snapper, S. B., Ostrov, D., Meredith, S. C., Miller, L. W., & Turner, J. R.
- Affiliations
- University of Chicago (US)
- Soochow University (CN)
- Brigham and Women's Hospital (US)
- Boston Children's Hospital (US)
- Vertex Pharmaceuticals (United States) (US)
- University of Florida (US)
- University of Illinois Chicago (US)
- Corresponding author
- Turner, Jerrold R.
- ORCID
- Venue
- Nature Medicine
- Published
- 2019-04
- Volume
- 25
- Issue
- 4
- Pages
- 690-700
- ISSN
- 1078-8956 (ISSN-L)
- 1546-170X
- PMC
- PMC6461392
- OpenAlex
- W2933961522
- Cited by
- 176
- References
- 56
- Citations by year
- 2026: 22 · 2025: 20 · 2024: 37 · 2023: 17 · 2022: 26 · 2021: 23 · 2020: 21 · 2019: 9
- FWCI
- 11.90
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Nature Medicine (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Figshare (submittedVersion, cc-by)
- University of Illinois Chicago
- Funders
- Crohn's and Colitis Foundation (310801)
- National Institute on Aging (R01AG048793)
- National Heart, Lung, and Blood Institute (T32HL007237)
- National Cancer Institute (P30CA014599)
- National Institute of General Medical Sciences (R01GM081030)
- National Institute of Diabetes and Digestive and Kidney Diseases (R56DK094954, R24DK099803, R01DK068271, P30DK034854, R01DK061931)
- Topics
- Health Sciences › Medicine › Gastroenterology › Inflammatory Bowel Disease
- Health Sciences › Medicine › Gastroenterology › Gastrointestinal motility and disorders
- Life Sciences › Neuroscience › Neurology › Barrier Structure and Function Studies
- Keywords
- myosin light chain kinase, epithelial barrier dysfunction, small molecule inhibitors, myosin light chain phosphorylation, inflammatory bowel disease, diarrhea, mucosal homeostasis
- MeSH terms
- Protein Domains, Actomyosin, Animals, Chronic Disease, Homeostasis, Humans, Inflammation, Intestinal Mucosa, Jejunum, Myosin-Light-Chain Kinase, Phosphorylation, Tumor Necrosis Factor-alpha, Inflammatory Bowel Diseases, Caco-2 Cells, Myosin Light Chains, Tight Junctions, Intracellular Space, Mice, Small Molecule Libraries
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
