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PAR2 Interrupts E-Cadherin Adhesion and Decreases the Transepithelial Resistance of Epithelia by Phosphorylating Tyrosines 489 and 654 of Beta-Catenin

¹ Department of Internal Medicine, University of Iowa, Iowa City, Iowa

Correspondence and requests for reprints should be addressed to D. Michael Shasby, M.D., Professor, Department of Internal Medicine, C33-I, University of Iowa College of Medicine, 200 Hawkins Drive, Iowa City, IA 52242. E-mail: michael-shasby{at}uiowa.edu

Activation of the type 2 protease–activated (PAR2) receptor interrupts E-cadherin adhesion and decreases the transepithelial resistance (TER) of epithelium (1). E-cadherin adhesive function depends on the association of E-cadherin with β-catenin, and this interaction is regulated by phosphorylation of tyrosines in β-catenin. We tested the hypothesis that loss of cadherin adhesion and compromise of epithelial barrier integrity upon activation of the PAR2 receptor is due to phosphorylation of tyrosines 489 and/or 654 in β-catenin. L-cells, stably expressing E-cadherin, and MDCK cells were transfected with FLAG-tagged wild-type (wt) or mutant β-catenin, converting tyrosine 142, 489, or 654 to phenylalanine (wt, Y142F, Y489F, or Y654F). PAR2 activation increased tyrosine phosphorylation of β-catenin. PAR2 activation interrupted adhesion to an immobilized E-cadherin–Fc fusion protein of L-E-cad and MDCK cells expressing wt or Y142F β-catenin, but did not interrupt adhesion of L-E-cad and MDCK cells expressing Y489F or Y654F β-catenins. PAR2 activation decreased the TER of monolayers of MDCK cells expressing wt or Y142F β-catenin by 40 to 45%. PAR2 activation did not decrease the TER of monolayers of MDCK cells expressing Y489F or Y654F β-catenin. We conclude that PAR2 interrupts E-cadherin adhesion by phosphorylating tyrosines 489 and/or 654 in β-catenin, and that PAR2 decreases the resistance of epithelium solely by interrupting E-cadherin adhesion. Intact E-cadherin adhesion is essential to lung epithelial and pulmonary microvascular barriers. β-catenin Y489 and Y654 are phosphorylated by Abl and Src kinases, respectively. Src-Abl inhibitors are clinically available and may provide a mechanism to limit the effects of inflammation on vital E-cadherin epithelial and endothelial barriers in the lung.

FOOTNOTES

Support: NHLBI HL33540 (D.M.S.).

Conflict of Interest Statement: M.C.W. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. S.S.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript. D.M.S. does not have a financial relationship with a commercial entity that has an interest in the subject of this manuscript.

(Received in original form July 17, 2007; accepted in final form October 16, 2007)

REFERENCES

1. Winter MC, Shasby SS, Ries DR, Shasby DM. PAR2 activation interrupts E-cadherin adhesion and compromises the airway epithelial barrier: protective effect of beta-agonists. Am J Physiol Lung Cell Mol Physiol 2006;291:L628–L635.[Abstract/Free Full Text]

This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Winter, M. C. Articles by Shasby, D. M. Search for Related Content PubMed Articles by Winter, M. C. Articles by Shasby, D. M.