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First published online 19 February 2008
doi: 10.1242/jcs.014878

Journal of Cell Science 121, 814-824 (2008)
Published by The Company of Biologists 2008
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Research Article

G{alpha}12 regulates protein interactions within the MDCK cell tight junction and inhibits tight-junction assembly

Ernesto Sabath1,*, Hideyuki Negoro1,*, Sarah Beaudry1, Manuel Paniagua1, Susanne Angelow2, Jagesh Shah1, Nicholas Grammatikakis3, Alan S. L. Yu2 and Bradley M. Denker1,{ddagger}

1 Renal Division, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
2 Nephrology Division, University of Southern California, Los Angeles, CA 90089, USA
3 Institute of Biology, National Centre for Scientific Research `Demokritos', Athens, Greece

{ddagger} Author for correspondence (e-mail: bdenker{at}rics.bwh.harvard.edu)

Accepted 11 December 2007

The polarized functions of epithelia require an intact tight junction (TJ) to restrict paracellular movement and to separate membrane proteins into specific domains. TJs contain scaffolding, integral membrane and signaling proteins, but the mechanisms that regulate TJs and their assembly are not well defined. G{alpha}12 (GNA12) binds the TJ protein ZO-1 (TJP1), and G{alpha}12 activates Src to increase paracellular permeability via unknown mechanisms. Herein, we identify Src as a component of the TJ and find that recruitment of Hsp90 to activated G{alpha}12 is necessary for signaling. TJ integrity is disrupted by G{alpha}12-stimulated Src phosphorylation of ZO-1 and ZO-2 (TJP2); this phosphorylation leads to dissociation of occludin and claudin 1 from the ZO-1 protein complex. Inhibiting Hsp90 with geldanamycin blocks G{alpha}12-stimulated Src activation and phosphorylation, but does not affect protein levels or the G{alpha}12–ZO-1 interaction. Using the calcium-switch model of TJ assembly and GST-TPR (GST-fused TPR domain of PP5) pull-downs of activated G{alpha}12, we demonstrate that switching to normal calcium medium activates endogenous G{alpha}12 during TJ assembly. Thrombin increases permeability and delays TJ assembly by activating G{alpha}12, but not G{alpha}13, signaling pathways. These findings reveal an important role for G{alpha}12, Src and Hsp90 in regulating the TJ in established epithelia and during TJ assembly.

Key words: Epithelial cells, G proteins, G12, Kidney, Tight junctions


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