Last Updated: 12/15/2008

Research Interests
Regulation of Tight Junctions and Paracellular Transport

Tight Junctions and Drug Delivery
Tight junctions limit the paracellular diffuse of therapeutic drugs across epithelia. A better understand of the molecular basis of the barrier would assist in design of chemotherapeutic drugs with better absorption across the gut, lung and out of blood vessels (e.g. the blood-brain barrier). One project in our laboratory is aimed at defining the molecules that restrict diffusion through the extracellular space at the tight junction. We have shown that a tetraspan protein family called claudins is responsible for the selective barrier properties of the junction including its ionic charge selectivity. We have shown that the many members of the claudin family are differentially expressed, strongly suggesting that each epithelium in the body has unique barrier properties. We are exploring in collaboration with members of the Pharmacy School ways to enhance the transepithelial delivery of therapeutic drugs based on matching the variable properties of each epithelium with drug chemistry. An obvious goal will be to enhance chemotherapy drug delivery across the blood-brain barrier to treat CNS tumors.

Background to Cancer-Related Research
A major project in our laboratory is aimed at understanding how Membrane-Associated Guanylate Kinase Homologs (MAGUKs) organize plasma membrane signaling complexes. MAGUKs are defined by having multiple domain including PDZ, SH3 and GUK domains. Some MAGUK proteins are known tumor suppressors (e.g. Drosophila, discs-large) or required for the proper signaling through receptor tyrosine kinases (C. elegans, Lin-2). We study three MAGUK proteins, ZO-1, 2 and 3, that are associated with the cytoplasmic surface of epithelial cell tight junctions. Although tight junctions are better known for creating a paracellular barrier between cells there is growing evidence that tight junctions, like all other forms of cell-cell contact, are involved in signaling. Although the role of ZO-MAGUKs in cell growth regulation is not yet directly demonstrated there are several intriguing hints. For example, the oncogenic potential of adenovirus type 9 E4-ORF1 requires its binding to ZO-2. Many pancreatic tumors transcribe a truncated form of ZO-2 from one specific alternative start site. We are presently investigating the cellular location and properties of the different forms of ZO-2. ZO-1 binds several transcription factors, and is down regulated in breast caner. There is evidence that ZO-1 interacts with the wnt/-catenin pathway and it over-expression in cultured cell stimulates cell growth rate.

Recent Accomplishments and Honors
Our most significant research accomplishment in the last 3 years has been to show that the claudin family of proteins form charge-selective channels through the tight junction. Because there are >25 claudins and they have different expression profiles throughout the body, this insight goes a long way to explaining why tissues differ their drug permeability. This work has been recognized by editorial reviews accompanying two of our papers and invitations to speak in an international forum.

2007 Distinquished Research Award, American Physiological Society

Selected recent research seminars:

FASEB, EB-2009, APS-Renal Section, New Orleans, April 20th, 2009

Digestive Diseases Week, Chicago, May 30th, 2009

The Physiological Society (UK), Newcastle upon
Tyne, UK, Sept. 7th, 2009

XXXVI International Congress of Physiological Sciences, Kyoto Japan, July 27th,2009

Experimental Biology-2008, ASIP/APS, San Diego, CA, April 7, 2008

Deutsche Charité Campus Benjamin Franklin, Berlin, Germany April 25-28, 2008

NIH Consensus Conference, NIDDK, Bethesda, MD March 25-26, 2008

Yale Department of Cell Biology, New Haven CT, May 28th, 2008

Center of Biomedical Research Excellence, Kansas State, Manhattan, KS, June 10th, 2008

Johns Hopkins School of Medicine, Medicine, Oct. 14th, 2008

The Emile Boulpaep Symposium, Yale, New Haven CT, Nov. 11th, 2008

Training
PhD, Biology, Harvard, 1979
MD, Harvard Medical School, 1983

Residency, Internal Medicine, Yale, 1983 - 86
Hepatology Fellowship, Yale, 1986 - 89
Diplomat, ABIM, 1986 -
Attending Physician, Yale, Internal Medicine and Hepatology, 1988 - 02

Publications
Willott E, Balda MS, Fanning AS, Jameson, B, Van Itallie, C. Anderson, JM. The tight junction protein ZO-1 is homologous to the Drosophila discs-large tumor suppressor protein of septate junctions. Proc Natl Acad Sci. 1993 90 (16):7834-7838.

Van Itallie, CM, Balda, MS, Anderson, JM. EGF induces ZO-1 translocation and tyrosine phosphorylation in A431 cells. J Cell Sci. 1995. 108:1735-1742.

Songyang, Z, Fanning, AS, Fu, C, Xu, J, Marfatia, S, Chishti, AH, Crompton, A, Chan, AC, Anderson, JM, Cantley, LC. Recognition of unique carboxyl-terminal motifs by distinct PDZ domains. Science. 1997 275:73-77.

Balda, MS, Anderson, JM, Matter, K. 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 1996 399:326-332.

Daniels, DL, Cohen, AR, Anderson, JM, Brunger, AT. Structural basis of Class II PDZ domain target recognition: Crystal structure of the hCASK PDZ domain. Nature Structural Biology 1998 5(4):317-324.

Cohen, A, Walther, Z, Marfatia, S, Chishti, A, Anderson, JM. hCASK/LIN-2 bind Syndecan-2 and protein 4.1 potentially forming a functional link between extracellular matrix and the cytoskeleton. J Cell Biology 1998 142(1):1-10.

Nix, SL, Chishti, AH, Anderson, JM, Walther, Z. hCASK and hDlg associate in epithelia, and their SH3 and guanylate kinase domains participate in both intramolecular and intermolecular interactions. J Biol Chem. 2000 275(52):41192-200.

Colegio, OR, McCrea, H, Rahner, C, Van Itallie, C, Anderson, JM. Claudins create charge-selective channels in the paracellular pathways of epithelial cells. Am. J. Physiol (Cell) 2002 283(1):C142-7.

Maday, S., Anderson, E., Chang, H.C., Shorter, J., Satoh, A, Sfakianos, J., Fölsch, H., Anderson, J.M., Walther, Z. and I. Mellman. 2008. A PDZ-binding motif controls basolateral targeting of syndecan-1 along the biosynthetic pathway in polarized epithelial cells. Traffic (in press).

Van Itallie C.M., Holmes, J., Bridges, A. and J.M. Anderson. 2008. Claudin-2-dependent changes in noncharged solute flux are mediated by the extracellular domains and require attachment to the PDZ-scaffold. Annals of the New York Academy of Sciences. (in press).

Van Itallie, C.M., Holmes, H., Bridges, A., Gookin, J., Coccaro, M., Dunworth, W., Colegio, O. and J.M. Anderson. 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, McClane, BA and JM Anderson. 2008. Structure of the Claudin-binding Domain of Clostridium perfringens Enterotoxin. J Biol Chem 4;283(1):268-74.

E-mail: jandersn@med.unc.edu
Telephone: 919-966-6411
FAX: 919-966-6413
Address: 266 Medical Sciences Research Bldg Chapel Hill, NC 27599-7545

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