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PNAS 104 (3): 819-822

Copyright © 2007 by the National Academy of Sciences.

BIOLOGICAL SCIENCES / CELL BIOLOGY

Regulation of epithelial tight junction assembly and disassembly by AMP-activated protein kinase

Bin Zheng, and Lewis C. Cantley*

Division of Signal Transduction, Beth Israel Deaconess Medical Center, and Department of Systems Biology, Harvard Medical School, Boston, MA 02115

Contributed by Lewis C. Cantley, November 16, 2006

Received for publication November 10, 2006.

Abstract: AMP-activated protein kinase (AMPK) is a serine/threonine protein kinase that plays an important role in maintaining cellular energy balance. The activity of AMPK is modulated both by the cellular AMP-to-ATP ratio and by upstream kinases. Recently, AMPK was shown to be phosphorylated and activated by LKB1, a protein kinase that plays a conserved role in epithelial polarity regulation in mammals and Drosophila. Here, we investigate the involvement of AMPK in the regulation of epithelial tight junction assembly and cell polarization in MDCK cells. We show that the level of AMPK phosphorylation increases during calcium-induced tight junction assembly and cell polarization and that this increase depends on the kinase activity of LKB1. Expression of a kinase-dead mutant of AMPK inhibits tight junction assembly as indicated by measurement of transepithelial resistance and analysis of ZO-1 localization to the tight junction after calcium switch. Conversely, 5-aminoimidizole-4-carboxamide riboside, an activator of AMPK, promotes transepithelial resistance development and tight junction assembly upon calcium switch. Furthermore, 5-aminoimidizole-4-carboxamide riboside partially protects the tight junctions from disassembly induced by calcium depletion. These results support an important role of AMPK in the regulation of epithelial tight junction assembly and disassembly and suggest an intriguing link between cellular energy status and tight junction function.

Key Words: 5-aminoimidizole-4-carboxamide riboside • LKB1 • transepithelial resistance • Zo-1

Author contributions: B.Z. and L.C.C. designed research; B.Z. performed research; B.Z. and L.C.C. analyzed data; and B.Z. and L.C.C. wrote the paper.

The authors declare no conflict of interest.

*To whom correspondence should be addressed at: Division of Signal Transduction, Beth Israel Deaconess Medical Center, 77 Avenue Louis Pasteur, Room 1052, Boston, MA 02115. E-mail: lewis_cantley{at}hms.harvard.edu

© 2007 by The National Academy of Sciences of the USA

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