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James M. Anderson, MD, PhD Education: PhD, Harvard
University 1979
Tight junctions: selectivity and regulation of the paracellular pathway
Tight junctions between epithelial and endothelial cells create selective barriers regulating paracellular transport of solutes, immune cells and drugs. The barrier varies widely among cell types in electrical resistance and behaves as if it is lined with pores showing selectivity for ionic charge and size. We study the molecular basis of the tight junction barrier and its selectivity with a focus on key proteins of the barrier, including ZO-1, occludin, tricellulin and members of the large claudin family. Our work is supported by the NIH (DK 45134; DK 61397) and the UNC Center for Gastrointestinal Biology and Disease (P30 DK 034987). Co-Investigators: Dr. Christina M. Van Itallie (Associate Professor of Medicine) and Dr. Alan Fanning (Associate Professor of Cell and Molecular Physiology), Jennifer Holmes, M.S.
Specific Research Areas: Basis of ionic charge and size selectivity of the tight junction with a special focus on regulation of the intestinal barrier in inflammation. Structural studies of claudins and a naturally occurring ligand, the Clostridia perfringens enterotoxin (CPE). Studies include biochemistry, mutagenesis, cell biology in cultured cell models, animal models and crystallography. Biology of occludin and tricellulin and their roles in organizing the tight junction barrier. Structural and cell biologic studies of ZO-1 and its role in tight junction scaffolding.
Van Itallie CM, Holmes J, Bridges A, Gookin JL, Coccaro MR, Proctor W, Colegio OR, Anderson JM. (2008) The density of small tight junction pores varies among cell types and is increased by expression of claudin-2. J Cell Sci. 121(Pt 3):298-305. Van Itallie CM, Betts L, Smedle, JG, McClane BA and Anderson JM. (2008) Structure of the claudin-binding domain of clostridia perfringens enterotoxin. J Biol Chem. 283(1):268-74. Jovov B, Van Itallie CM, Shaheen NJ, Carson JL, Gambling M, Anderson JM, Orlando RC. (2007) Claudin-18: A Dominant Tight Junction Protein in Barrett's Esophagus and Likely Contributor to its Acid Resistance. Am J Physiol Gastrointest Liver Physiol. 293(6):G1106-13. Fanning AS, Lye MF, Anderson JM, Arnon L. (2007) Domain swapping within PDZ2 is responsible for dimerization of ZO proteins. J Biol Chem. 28;282(52):37710-6. Robertson SL, Smedley JG 3rd, Singh U, Chakrabarti G, Van Itallie CM, Anderson JM, McClane BA. (2007) Compositional and stoichiometric analysis of Clostridium perfringens enterotoxin complexes in Caco-2 cells and claudin 4 fibroblast transfectants. Cell Microbiol. 9(11):2734-55. Fanning AS, Little BP, Rahner C, Utepbergenov D, Walther Z and Anderson JM . (2007) The Unique-5 and -6 Motifs of ZO-1 Regulate Tight Junction Strand Localization and Scaffolding Properties. Molecular Biology of the Cell 18(3):721-31. Utepberganov D, Fanning AS and Anderson JM. (2006) Dimerization of the scaffolding protein ZO-1 through the second PDZ domain. Journal of Biological Chemistry. Aug 25; 281(34):24671-7. Van Itallie CM, Rogan S, Yu A, Seminario L Holmes J and Anderson JM. (2006) Two splice variants of claudin-10 in the kidney create paracellular pores with different ion selectivities. Am J Physiol Renal Physiol 291: 1288-1299. Holmes J, Van Itallie CM, Rasmussen JE and Anderson JM. (2006) Claudin Profiling in the Mouse during Postnatal Intestinal Development and along the Gastrointestinal Tract Reveals Complex Expression Patterns. Gene Expression Patterns: A section of Mechanisms of Development. Aug 6, 6: 581-588. Van Itallie CM, Gambling TM, Carson JL and Anderson JM. (2005) Palmitoylation of claudins is required for efficient tight junction localization and barrier function. Journal of Cell Science. 118(Pt 7):1427-36. Li Y, Fanning AS, Anderson JM and Lavie A. (2005) Structure of the Conserved C-terminal domain of occludin: Identification of the ZO-1 binding surface. Journal of Molecular Biology. 352(1):151-64. Van Itallie, C.M., Colegio, O.R., J.M. Anderson. (2004) The cytoplasmic tails of claudins influence tight junction barrier properties through effects on protein stability. J Membrane Biol. 199: 1-10. Mitic, L.L., Unger, V.M. and J.M. Anderson. 2003. Expression, solubilization and biochemical characterization of the tight junction transmembrane protein claudin-4. Protein Science Feb;12(2):218-27. Colegio, O.R., Van Itallie, C.M., Rahner, C. and J.M. Anderson. 2003. Claudin extracellular domains determine paracellular charge selectivity and transepithelial resistance but not tight junction fibril architecture. Am. J. Physiol (Cell) 284(6):C1346-54. Van Itallie, C.M., Fanning, A.S and J. M. Anderson. 2003. Reversal of charge selectivity in cation or anion selective epithelial lines by expression of different claudins. Am. J. Physiol Renal Physiol. 285(6):F1078-84. Ben-Yosef, T. Belyantseva, I.A., Saunders, T.L., Hughes, E.D., Kawamoto, K., Van Itallie, C.M., Beyer, L.A., Halsey, K., Gardner, D.J., Wilcox, E.R., Rasmussen, J., Anderson, J.M., Dolan, D.F., Forge, A., Raphael, Y., Camper, S.A. and T.B. Friedman. 2003. Claudin 14 knockout mice, a model for autosomal recessive deafness DFNB29, are deaf due to cochlear hair cell degeneration. Human Mol Gen 12(16): 2049-2061. Colegio, O.R., McCrea, H., Rahner, C., Van Itallie, C., and J.M. Anderson. 2002. Claudins create charge-selective channels in the paracellular pathways of epithelial cells. Am. J. Physiol (Cell) 283(1):C142-7. Fanning, A.S., Ma, T. and J.M. Anderson. 2002. Isolation and functional characterization of the actin binding region in the tight junction proteins ZO-1. FASEB J. Nov;16(13):1835-1837. Rahner, C., Mitic, L.L. and J.M. Anderson. 2001. Heterogeneity in expression and subcellular localization of claudins 2, 3, 4 and 5 in the rat liver, pancreas and gut. Gastroenterology 120:411-422. Van Itallie, C., Rahner, C. and J.M. Anderson. 2001. Regulated expression of claudin-4 in MDCK cells decreases paracellular conductance through a selective decrease in sodium permeability. J Clin Invest 107(10):1319-27. Singh, U., Mitic, L.L., Wieckowski, E., Anderson , J.M. and McClane. 2001. Comparative biochemical and immunocytochemical studies reveal differences in the effects of Clostridium perfringens enterotoxin on polarized CaCo-2 cells versus vero cells. J Biol Chem Sept. 7: 276(36):33402-12. Sheth, B., Moran, B., Anderson, J.M. and T.P. Fleming. 2000. Post-translational control of occludin membrane assembly in mouse trophectoderm: A mechanism to regulate the timing of tight junction biogenesis and blastocyst formation. Development 127:831-840. Nix, S.L., Chishti, A.H., Anderson , J.M. and Z. Walther. 2000. hCASK and hDlg associate in epithelia, and their SH3 and guanylate kinase domains participate in both intramolecular and intermolecular interactions. J Biol Chem 275(52):41192-200. Medina, R., Anderson, J.M. and Van Itallie, C.M. 2000. Contribution of the extracellular loops of occludin to targeting to the tight junction. J Memb Biol 178(3):235-47. Singh, U., Van Itallie, C.M., Mitic, L.L., Anderson , J.M. and B.A. McClane. 2000. CaCo-2 cells treated with clostridium perfringens enterotoxin form multiple large complex species, one of which contains the tight junction protein occludin. J Biol Chem 275:18407-18417. Van Itallie, C.M. and J.M. Anderson. 1999. Tight junction protein ZO-1 isoforms (α+ and β-) show differential extractability and EGF-induced tyrosine phosphorylation in A431 cells. Protoplasma 206:201-218. Mitic, L.L., Van Itallie, C.M., and J.M. Anderson. 1999. Multi-step assembly of the tight junction: implications for intestinal barrier regulation and disease. In: Intestinal Mucosa and its Diseases. Kluwer Academic Pub 110:301-309. Lapierre, L.A., Tuma, P.L., Navarre, J., Goldenring, J.R. and J.M. Anderson. 1999. VAP33 localizes to both an intracellular vesicle population with occludin at the tight junction. J Cell Sci 112:3723-3732. Mitic, L.L., Schneeberger, E.E., Fanning, A.S., and J.M. Anderson. 1999. Connexin-occludin chimeras containing the ZO-1 binding domain of occludin localize at MDCK tight junctions and NRK cell contacts. J Cell Biol 146(3)683-693. Daniels, D.L., Cohen, A.R., Anderson, J.M., and A.T. Brunger. 1998. Structural basis of Class II PDZ domain target recognition: Crystal structure of the hCASK PDZ domain. Nature Structural Biology 5(4):317-324. Cohen, A., Walther, Z., Marfatia, S., Chishti, A. and Anderson, J.M. 1998. hCASK/LIN-2 bind Syndecan-2 and protein 4.1 potentially forming a functional link between extracellular matrix and the cytoskeleton. J Cell Biology 142(1):1-10. Fanning, A.S., Jesaitus, L., Jamieson, B. and J.M. Anderson. 1998. The tight junction protein ZO-1 establishes a link between the transmembrane protein occluding and the actin cytoskeleton. J Biological Chemistry 273:29745-29753. Van Itallie, C.M. and J.M. Anderson. 1997. Occludin confers adhesiveness when expressed in fibroblasts. J Cell Sci 110:1113-1121. Blum, M.S., Toninelli, E., Anderson, J.M., Balda, M.S., Zhou, J., O'Donnell, L., Pardi, R. and Bender, J.R. 1997. Cytoskeletal rearrangement mediates human microvascular endothelial tight junction modulation by cytokines. Amer J Physiol 273:H286-H294. Songyang, Z., Fanning, A.S., Fu, C., Xu, J., Marfatia, S.M., Chishti, A.H., Crompton, A., Chan, A.C., Anderson, J.M. and L.C. Cantley. 1997. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science 275:73-77. Pelletier, R-M, Okawara, Y., Vitale, M.L., and J.M. Anderson. 1997. Differential distribution of the tight-junction-associated protein ZO-1 a + and a - isoforms in guinea pig Sertoli cells: A possible association with F-actin and G-actin. Biol Reprod, 57(2)367-376. Sheth, B., Fesenko, I., Collins, J.E., Moran, B., Wild, A.E., Anderson, J.M., Fleming, T.P. 1997. Tight junction assembly during mouse blastocyst formation is regulated by late expression of ZO-1 a + isoform. Development 124:2027-2037. Balda, M.S., Anderson, J.M., Matter, K. 1996. The SH3 domain of the tight junction protein Z0-1 binds to a serine protein kinase that phosphorylates a region C-terminal to this domain. FEBS Letters 399:326-332.
Anderson, J.M. and C.M. Van Itallie. 2007. The molecular physiology of the tight junction. The Journal of Physiology. (invited Topical Review). Van Itallie, CM and JM Anderson. 2006. Claudins and epithelial paracellular transport. Annual Review of Physiology. ed. G. Giebisch, Annual Reviews, Palo Alto CA 68: 1-27. Van Itallie, CM and JM Anderson. 2004. The Molecular Physiology of Tight Junction Pores. Physiology 19:331-338. Anderson, JM, CM Van Itallie and AS Fanning. 2004. Setting up a selective barrier at the apical junction complex. Current Opinion in Cell Biology 16:1–6. Van Itallie, C.M. and J.M. Anderson. 2004. The Role of Claudins in Determining Paracellular Charge Selectivity. Proc. Am. Thoracic Soc. 1:38-41. Anderson, J.M. and K. Kowdly. 2002. Synopsis for the Yale workshop on hepatocellular carcinoma. J Clin Gastroenterol. 2002 Nov-Dec 35(5):S152-3. Anderson, J.M. 2001. Molecular structure of tight junctions and their role in epithelial transport. News Physiol Sci. 16:126-30. Anderson, J.M. 2000. Maintaining a defense as the injured leave the field: apoptosis and barrier function in the intestine. Gastroenterology 119(6):1783-7. Mitic, L.L., Van Itallie, C.M. and J.M. Anderson. 2000. Molecular Physiology and Pathophysiology: I. Tight junction structure and function: lessons of tight junctions from mutant animals and proteins. Amer J Physiol 279:G250-254. Fanning, A.S. Mitic, L. and J.M. Anderson. 1999 (Invited Review). Transmembrane proteins in the tight junction barrier. J Am Soc Nephrology 10:1337-1345. Fanning, A.S. and J.M. Anderson. 1999. Protein modules as organizers of membrane structure. Current Opinion in Cell Biology. Aug. 11(4):432-439. Fanning, A.S. and J.M. Anderson. 1999. PDZ domains: fundamental building blocks in the organization of protein complexes at the plasma membrane. J Clinical Investigation, 103(6):767-772. Anderson, J.M. and C.M. Van Itallie. 1999. Closing in on the seal. Curr Biol, 9(24):R922-4. Chishti, A.H., Kim, A.C., Lutchman, M., Marfatia, S.M., Jindal, H., Chasis, A. Conboy, J.G., Mohandas, N., Benz, E.J., Rouleau, G.A., Low, P.S., Bretscher, A., Gusella, J.F., Solomon, F., Fehon, R.G., Marchesi, V.T., Louvard, D., Tsukita, S., Tonks, N.K., Anderson, J.M., Bryant, P.J., and Hoover, K.B. 1998. The FERM domain: A unique module involved in the linkage of cytoplasmic proteins to the membrane. Trends in Biological Sciences 23:281-282. Fanning, A.S. and J.M. Anderson. 1996. Protein-protein interactions: PDZ domain networks. Current Biology 6(11)1385-1388. Anderson, J.M. 1996. MAGUK magic. Current Biology 6(4):326-329. Anderson, J.M. 1996. Leaky junctions and cholestasis: A tight correlation. Gastroenterology 110(5):1662-1665.
Ma, T and J.M. Anderson. 2005. Tight Junctions and the Intestinal Barrier. In Physiology of the Gastrointestinal Tract, ed. Leonard R. Johnson. Elsevier Publishing Company. Van Itallie, C.M. and J.M. Anderson. 2004. Tight Junction Channels. In Selected Topics on Tight Junctions, ed. L. Gonzalez-Mariscal. Landes. Madara, J.L. and J.M. Anderson. 2003. Epithelia: Biologic Principles of Organization, in Textbook of Gastroenterology, ed. Tadataka Yamada; associate eds, David H. Alpers [et al.]-4th edition. Lippincott Williams & Wilkins. Anderson, J.M. and C.M. Van Itallie. 2000. Molecular structure and regulation of tight junctions. In Gastrointestinal Transport: Molecular Physiology (Current Topics in Membranes), eds. K. Barrett and M. Donowitz, San Diego: Academic Press. Vol. 50:163-182. Fanning, A.S. and J.M. Anderson. 1998. PDZ domains and the formation of protein networks at the plasma membrane. In Current Topics in Microbiology and Immunology: Protein Modules in Signal Transduction, ed. Anthony Pawsons. Springer: New York. 228:209-233. Mitic, L. and J.M. Anderson. 1998. Molecular architecture of tight junctions. In Annual Reviews of Physiology. Annual Reviews Inc. 60:121-142. Anderson, J.M. and Fanning, A.S. 1998. Cholestasis associated with alterations in the actin cytoskeleton and tight junction barrier. In Cholestatic Liver Diseases, Eds. M.P. Manns, J.L. Boyer, P.L.M. Jansen, and J. Reichen. Kluwer Academic Pub. 102:29-35. Fanning, A.S., Lapierre, L.A., Brecher, A.R., Van Itallie, C.M. and J.M. Anderson. 1997. Protein interactions in the tight junction: the role of MAGUK proteins in regulating tight junction organization and function. In Membrane Protein Cytoskeleton Interactions (Current Topics in Membranes), ed. W.J. Nelson, Academic Press, Vol. 43:211-235.
Cereijido, M. and J.M. Anderson. 2001. Tight Junctions, 2nd edition. Boca Raton, FL: CRC Press.
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