ATP depletion increases tyrosine phosphorylation of beta-catenin and plakoglobin in renal tubular cells

This study examines the hypothesis that the loss of integrity of the juncti onal complex induced by ATP depletion is related to alterations in tyrosine phosphorylation of the adherens junction proteins beta-catenin and plakogl obin. ATP depletion of cultured mouse proximal tubular (MPT) cells induces a marked increase in tyrosine phosphorylation of both beta-catenin and plak oglobin. The tyrosine phosphatase inhibitor vanadate has the same effect in ATP-replete (control) monolayers, whereas genistein, a tyrosine kinase inh ibitor, reduces phosphorylation of both proteins in ATP-replete monolayers and prevents the hyperphosphorylation of these proteins with ATP depletion. This study also demonstrates that the fall in the transepithelial resistan ce of MPT monolayers induced by ATP depletion can be reproduced by treatmen t of ATP-replete monolayers with vanadate, whereas genistein sutbstantially ameliorates the fall in transepithelial resistance induced by ATP depletio n. Also, using immunofluorescence microscopy it was demonstrated that ATP d epletion results in a marked diminution of E-cadherin staining in the basol ateral membrane of MPT cells. Vanadate mimics this effect of ATP depletion, whereas genistein ameliorates the reduction in the intensity of E-cadherin staining induced by ATP depletion. Because it is has been well established that hyperphosphorylation of the catenins :leads to dissociation of the ad herens junction and to dysfunction of the junctional complex, it is propose d that the increase in tyrosine phosphorylation of catenins observed in MPT cells during ATP depletion contributes to the loss of function of the junc tional complex associated with sublethal injury.