Isoform-selective control of the epithelial barrier

independent of immunosuppression

Loading structure 6C6M from the RCSB Protein Data Bank

Surface pocket (computed): waiting for structure

Illustrative simulation: compounds and scores are generated for visualization, not experimental data. IgCAM3 domain of human MLCK1 · PDB 6C6M · X-ray 2.5 Å

References

  1. Graham WV, He W, Marchiando AM, Zha J, Singh G, Li HS, Biswas A, Ong MLDM, Jiang ZH, Choi W, Zuccola H, Wang Y, Griffith J, Wu J, Rosenberg HJ, Wang Y, Snapper SB, Ostrov D, Meredith SC, Miller LW, Turner JR. Intracellular MLCK1 diversion reverses barrier loss to restore mucosal homeostasis. Nat Med. 2019;25(4):690-700. doi:10.1038/s41591-019-0393-7 · PMID 30936544
  2. Graham WV, Wang F, Clayburgh DR, Cheng JX, Yoon B, Wang Y, Lin A, Turner JR. Tumor necrosis factor-induced long myosin light chain kinase transcription is regulated by differentiation-dependent signaling events. Characterization of the human long myosin light chain kinase promoter. J Biol Chem. 2006;281(36):26205-15. doi:10.1074/jbc.M602164200 · PMID 16835238
  3. Graham WV, Magis AT, Bailey KM, Turner JR, Ostrov DA. Crystallization and preliminary X-ray analysis of the human long myosin light-chain kinase 1-specific domain IgCAM3. Acta Crystallogr Sect F Struct Biol Cryst Commun. 2011;67(Pt 2):221-3. doi:10.1107/S1744309110050323 · PMID 21301090
  4. Wang F, Graham WV, Wang Y, Witkowski ED, Schwarz BT, Turner JR. Interferon-gamma and tumor necrosis factor-alpha synergize to induce intestinal epithelial barrier dysfunction by up-regulating myosin light chain kinase expression. Am J Pathol. 2005;166(2):409-19. doi:10.1016/s0002-9440(10)62264-x · PMID 15681825
  5. Marchiando AM, Shen L, Graham WV, Weber CR, Schwarz BT, Austin JR, Raleigh DR, Guan Y, Watson AJ, Montrose MH, Turner JR. Caveolin-1-dependent occludin endocytosis is required for TNF-induced tight junction regulation in vivo. J Cell Biol. 2010;189(1):111-26. doi:10.1083/jcb.200902153 · PMID 20351069
  6. Marchiando AM, Shen L, Graham WV, Edelblum KL, Duckworth CA, Guan Y, Montrose MH, Turner JR, Watson AJ. The epithelial barrier is maintained by in vivo tight junction expansion during pathologic intestinal epithelial shedding. Gastroenterology. 2011;140(4):1208-1218.e1-2. doi:10.1053/j.gastro.2011.01.004 · PMID 21237166
  7. Wang F, Schwarz BT, Graham WV, Wang Y, Su L, Clayburgh DR, Abraham C, Turner JR. IFN-gamma-induced TNFR2 expression is required for TNF-dependent intestinal epithelial barrier dysfunction. Gastroenterology. 2006;131(4):1153-63. doi:10.1053/j.gastro.2006.08.022 · PMID 17030185
  8. Russo JM, Florian P, Shen L, Graham WV, Tretiakova MS, Gitter AH, Mrsny RJ, Turner JR. Distinct temporal-spatial roles for rho kinase and myosin light chain kinase in epithelial purse-string wound closure. Gastroenterology. 2005;128(4):987-1001. doi:10.1053/j.gastro.2005.01.004 · PMID 15825080
  9. Owens SE, Graham WV, Siccardi D, Turner JR, Mrsny RJ. A strategy to identify stable membrane-permeant peptide inhibitors of myosin light chain kinase. Pharm Res. 2005;22(5):703-9. doi:10.1007/s11095-005-2584-9 · PMID 15906163
  10. Marchiando AM, Graham WV, Turner JR. Epithelial barriers in homeostasis and disease. Annu Rev Pathol. 2010;5:119-44. doi:10.1146/annurev.pathol.4.110807.092135 · PMID 20078218
  11. Graham WV, Marchiando AM, Shen L, Turner JR. No static at all. Ann N Y Acad Sci. 2009;1165:314-22. doi:10.1111/j.1749-6632.2009.04050.x · PMID 19538322
  12. He WQ, Wang J, Sheng JY, Zha JM, Graham WV, Turner JR. Contributions of Myosin Light Chain Kinase to Regulation of Epithelial Paracellular Permeability and Mucosal Homeostasis. Int J Mol Sci. 2020;21(3). doi:10.3390/ijms21030993 · PMID 32028590