Regulation of Epithelial Tight Junction Assembly and Disassembly by AMP-activated Protein Kinase

Overview

Journal Proc Natl Acad Sci U S A

Specialty Science

Date 2007 Jan 6

PMID 17204563

Citations 142

Authors

Bin Zheng

Lewis C Cantley

Affiliations

Soon will be listed here.

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.

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References

Nava P, Lopez S, Arias C, Islas S, Gonzalez-Mariscal L . The rotavirus surface protein VP8 modulates the gate and fence function of tight junctions in epithelial cells. J Cell Sci. 2004; 117(Pt 23):5509-19. DOI: 10.1242/jcs.01425. View

Bilder D . Epithelial polarity and proliferation control: links from the Drosophila neoplastic tumor suppressors. Genes Dev. 2004; 18(16):1909-25. DOI: 10.1101/gad.1211604. View

Rappleye C, Tagawa A, Le Bot N, Ahringer J, Aroian R . Involvement of fatty acid pathways and cortical interaction of the pronuclear complex in Caenorhabditis elegans embryonic polarity. BMC Dev Biol. 2003; 3:8. PMC: 270048. DOI: 10.1186/1471-213X-3-8. View

Spicer J, Ashworth A . LKB1 kinase: master and commander of metabolism and polarity. Curr Biol. 2004; 14(10):R383-5. DOI: 10.1016/j.cub.2004.05.012. View

Hawley S, Boudeau J, Reid J, Mustard K, Udd L, Makela T . Complexes between the LKB1 tumor suppressor, STRAD alpha/beta and MO25 alpha/beta are upstream kinases in the AMP-activated protein kinase cascade. J Biol. 2003; 2(4):28. PMC: 333410. DOI: 10.1186/1475-4924-2-28. View

Gumbiner B, Simons K . A functional assay for proteins involved in establishing an epithelial occluding barrier: identification of a uvomorulin-like polypeptide. J Cell Biol. 1986; 102(2):457-68. PMC: 2114088. DOI: 10.1083/jcb.102.2.457. View

Farquhar M, Palade G . Junctional complexes in various epithelia. J Cell Biol. 1963; 17:375-412. PMC: 2106201. DOI: 10.1083/jcb.17.2.375. View

Luo Z, Saha A, Xiang X, Ruderman N . AMPK, the metabolic syndrome and cancer. Trends Pharmacol Sci. 2005; 26(2):69-76. DOI: 10.1016/j.tips.2004.12.011. View

Jones R, Plas D, Kubek S, Buzzai M, Mu J, Xu Y . AMP-activated protein kinase induces a p53-dependent metabolic checkpoint. Mol Cell. 2005; 18(3):283-93. DOI: 10.1016/j.molcel.2005.03.027. View

10.

Kahn B, Alquier T, Carling D, Grahame Hardie D . AMP-activated protein kinase: ancient energy gauge provides clues to modern understanding of metabolism. Cell Metab. 2005; 1(1):15-25. DOI: 10.1016/j.cmet.2004.12.003. View

11.

Hawley S, Pan D, Mustard K, Ross L, Bain J, Edelman A . Calmodulin-dependent protein kinase kinase-beta is an alternative upstream kinase for AMP-activated protein kinase. Cell Metab. 2005; 2(1):9-19. DOI: 10.1016/j.cmet.2005.05.009. View

12.

Woods A, Dickerson K, Heath R, Hong S, Momcilovic M, Johnstone S . Ca2+/calmodulin-dependent protein kinase kinase-beta acts upstream of AMP-activated protein kinase in mammalian cells. Cell Metab. 2005; 2(1):21-33. DOI: 10.1016/j.cmet.2005.06.005. View

13.

Hurley R, Anderson K, Franzone J, Kemp B, Means A, Witters L . The Ca2+/calmodulin-dependent protein kinase kinases are AMP-activated protein kinase kinases. J Biol Chem. 2005; 280(32):29060-6. DOI: 10.1074/jbc.M503824200. View

14.

Matter K, Aijaz S, Tsapara A, Balda M . Mammalian tight junctions in the regulation of epithelial differentiation and proliferation. Curr Opin Cell Biol. 2005; 17(5):453-8. DOI: 10.1016/j.ceb.2005.08.003. View

15.

Utech M, Ivanov A, Samarin S, Bruewer M, Turner J, Mrsny R . Mechanism of IFN-gamma-induced endocytosis of tight junction proteins: myosin II-dependent vacuolarization of the apical plasma membrane. Mol Biol Cell. 2005; 16(10):5040-52. PMC: 1237102. DOI: 10.1091/mbc.e05-03-0193. View

16.

Alessi D, Sakamoto K, Bayascas J . LKB1-dependent signaling pathways. Annu Rev Biochem. 2006; 75:137-63. DOI: 10.1146/annurev.biochem.75.103004.142702. View

17.

Watts J, Morton D, Bestman J, Kemphues K . The C. elegans par-4 gene encodes a putative serine-threonine kinase required for establishing embryonic asymmetry. Development. 2000; 127(7):1467-75. DOI: 10.1242/dev.127.7.1467. View

18.

Chen M, Pothoulakis C, Lamont J . Protein kinase C signaling regulates ZO-1 translocation and increased paracellular flux of T84 colonocytes exposed to Clostridium difficile toxin A. J Biol Chem. 2001; 277(6):4247-54. DOI: 10.1074/jbc.M109254200. View

19.

Martin S, St Johnston D . A role for Drosophila LKB1 in anterior-posterior axis formation and epithelial polarity. Nature. 2003; 421(6921):379-84. DOI: 10.1038/nature01296. View

20.

Amieva M, Vogelmann R, Covacci A, Tompkins L, Nelson W, Falkow S . Disruption of the epithelial apical-junctional complex by Helicobacter pylori CagA. Science. 2003; 300(5624):1430-4. PMC: 3369828. DOI: 10.1126/science.1081919. View