Polycystin-1 and Gα12 regulate the cleavage of E-cadherin in kidney epithelial cells

Interaction of polycystin-1 (PC1) and G alpha 12 is important for development of kidney cysts in autosomal dominant polycystic kidney disease (ADPKD). The integrity of cell polarity and cell-cell adhesions (mainly E-cadherin-mediated adherens junction) is altered in the renal epithelial cells of ADPKD. However, the key signaling pathway for this alteration is not fully understood. Madin-Darby canine kidney (MDCK) cells maintain the normal integrity of epithelial cell polarity and adherens junctions. Here, we found that deletion of Pkd1 increased activation of G alpha 12, which then promoted the cystogenesis of MDCK cells. The morphology of these cells was altered after the activation of G alpha 12. By using liquid chromatography-mass spectrometry, we found several proteins that could be related this change in the extracellular milieu. E-cadherin was one of the most abundant peptides after active G alpha 12 was induced. G alpha 12 activation or Pkd1 deletion increased the shedding of E-cadherin, which was mediated via increased ADAM10 activity. The increased shedding of E-cadherin was blocked by knockdown of ADAM10 or specific ADAM10 inhibitor GI254023X. Pkd1 deletion or G alpha 12 activation also changed the distribution of E-cadherin in kidney epithelial cells and caused beta-catenin to shift from cell membrane to nucleus. Finally, ADAM10 inhibitor, GI254023X, blocked the cystogenesis induced by PC1 knockdown or G alpha 12 activation in renal epithelial cells. Our results demonstrate that the E-cadherin/beta-catenin signaling pathway is regulated by PC1 and G alpha 12 via ADAM10. Specific inhibition of this pathway, especially ADAM10 activity, could be a novel therapeutic regimen for ADPKD.