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Articles in PresS, published online ahead of print January 9, 2002
Am J Physiol Cell Physiol, 10.1152/ajpcell.00288.2001
Submitted on June 25, 2001
Accepted on January 7, 2002
1 Center for Experimental Therapeutics, Brigham and Women's Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: dlaw{at}zeus.bwh.harvard.edu.
Epithelial permeability is tightly regulated by intracellular messengers. Critical to maintaining barrier integrity is the formation of tight junction complexes. A number of signaling pathways have been implicated in tight junction biogenesis, however, the precise molecular mechanisms are not fully understood. A growing body of evidence suggests a role for intracellular cyclic AMP (cAMP) in tight junction assembly. Using an epithelial model, we investigated the role of cAMP signal transduction in barrier recovery following Ca2+ switch. Our data demonstrate that elevation of intracellular cAMP levels significantly enhanced barrier recovery following Ca2+ switch. Parallel experiments revealed that epithelial barrier recovery is diminished by H89, a specific and potent inhibitor of cAMP-dependent protein kinase (PKA) activity. Of the possible PKA effector proteins, the vasodilator-stimulated phosphoprotein (VASP) is an attractive candidate since it has been implicated in actin binding and crosslinking functions. We therefore hypothesized that VASP may play a role in the cAMP-mediated regulation of epithelial junctional biogenesis following Ca2+ switch. We demonstrate here that VASP is phosphorylated via a PKA-dependent process under conditions which enhance barrier recovery. Confocal laser scanning microscopy studies revealed that VASP localizes with ZO-1 at the tight junction and at cell-cell borders, and that phospho-VASP appears at the junction following Ca2+ switch. Subsequent transfection studies utilizing epithelial cells expressing truncated forms of VASP abnormal in oligomerization or actin binding activity revealed a functional diminution of barrier recovery following Ca2+ chelation. Our present studies suggest that VASP may provide a link between cyclic AMP signal transduction and epithelial permeability.
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