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JCS ePress online publication date 19 Feb 2008
doi: 10.1242/jcs.014878

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Research Article

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


Ernesto Sabath, Hideyuki Negoro, Sarah Beaudry, Manuel Paniagua, Susanne Angelow, Jagesh Shah, Nicholas Grammatikakis, Alan S.L. Yu, and Bradley M. Denker*
* Author for correspondence (e-mail: bdenker{at}rics.bwh.harvard.edu)

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.


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