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12 Regulates Epithelial Cell Junctions Through Src Tyrosine Kinases
1 Medicine, Brigham and Women's Hospital, Boston, MA, USA; Harvard Medical School, Boston, MA, USA
2 Surgery, Children's Hospital, Boston, MA, USA
* To whom correspondence should be addressed. E-mail: bdenker{at}rics.bwh.harvard.edu.
Regulation and assembly of the epithelial cell junctional complex involves multiple signaling mechanisms including heterotrimeric G-Proteins. Recently, we demonstrated that G
12 binds to the tight junction scaffolding protein ZO-1 through the SH3 domain, and activated G12 increases paracellular permeability in MDCK cells (Meyer et al., J. Biol. Chem 277; 24855 (2002)). In the present studies, we explore the effects of G12 expression on tight and adherens junction proteins and examine downstream signaling pathways. By confocal microscopy we detect disrupted tight and adherens junction proteins with increased actin stress fibers in constitutively active G12 (QL) expressing MDCK cells. The normal distribution of ZO-1 and Na/K-ATPase was altered in QL12-MDCK cells consistent with loss of polarity. We found that the tyrosine kinase inhibitor genistein and the Src specific inhibitor PP-2 reversibly abrogated the QL12 phenotype on the junctional complex. Junctional protein localization was preserved in PP-2 or genistein treated, QL12 expressing cells, and the increase in paracellular permeability as measured by TER and [H]3-mannitol flux was prevented by the inhibitors. Src activity was increased in QL12-MDCK cells as assessed by Src autophosphorylation, and 
-catenin tyrosine phosphorylation was also increased, although there was no detectable increase in Rho activity. Taken together, these results indicate that G12 regulates MDCK cell junctions, in part, through Src tyrosine kinase pathways.
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