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Am J Physiol Lung Cell Mol Physiol 293: L1321-L1331, 2007. First published September 7, 2007; doi:10.1152/ajplung.00443.2006
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Microtubule dynamics and Rac-1 signaling independently regulate barrier function in lung epithelial cells

Magdalena J. Lorenowicz,1 Mar Fernandez-Borja,1 Anne-Marieke D. van Stalborch,1 Marian A. J. A. van Sterkenburg,2 Pieter S. Hiemstra,2 and Peter L. Hordijk1

1Sanquin Research and Landsteiner Laboratory, Academic Medical Center, University of Amsterdam, Amsterdam; and 2Department of Pulmonology, Leiden University Medical Center, Leiden, The Netherlands

Submitted 9 November 2006 ; accepted in final form 4 September 2007

Cadherin-mediated cell-cell adhesion controls the morphology and function of epithelial cells and is a critical component of the pathology of chronic inflammatory disorders. Dynamic interactions between cadherins and the actin cytoskeleton are required for stable cell-cell contact. Besides actin, microtubules also target intercellular, cadherin-based junctions and contribute to their formation and stability. Here, we studied the role of microtubules in conjunction with Rho-like GTPases in the regulation of lung epithelial barrier function using real-time monitoring of transepithelial electrical resistance. Unexpectedly, we found that disruption of microtubules promotes epithelial cell-cell adhesion. This increase in epithelial barrier function is accompanied by the accumulation of beta-catenin at cell-cell junctions, as detected by immunofluorescence. Moreover, we found that the increase in cell-cell contact, induced by microtubule depolymerization, requires signaling through a RhoA/Rho kinase pathway. The Rac-1 GTPase counteracts this pathway, because inhibition of Rac-1 signaling rapidly promotes epithelial barrier function, in a microtubule- and RhoA-independent fashion. Together, our data suggest that microtubule-RhoA-mediated signaling and Rac-1 control lung epithelial integrity through counteracting independent pathways.

RhoA; cell-cell contact; transepithelial resistance


Address for reprint requests and other correspondence: P. L. Hordijk, Sanquin Research and Landsteiner Laboratory, Academic Medical Centre, Univ. of Amsterdam, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands (e-mail: p.hordijk{at}sanquin.nl)






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