RESUMO
ß-Catenin functions as an adherens junction protein for cell-cell adhesion and as a signaling protein. ß-catenin function is dependent on its stability, which is regulated by protein-protein interactions that stabilize ß-catenin or target it for proteasome-mediated degradation. In this study, we show that ß-catenin stability is regulated by intracellular pH (pHi) dynamics, with decreased stability at higher pHi in both mammalian cells and Drosophila melanogaster ß-Catenin degradation requires phosphorylation of N-terminal residues for recognition by the E3 ligase ß-TrCP. While ß-catenin phosphorylation was pH independent, higher pHi induced increased ß-TrCP binding and decreased ß-catenin stability. An evolutionarily conserved histidine in ß-catenin (found in the ß-TrCP DSGIHS destruction motif) is required for pH-dependent binding to ß-TrCP. Expressing a cancer-associated H36R-ß-catenin mutant in the Drosophila eye was sufficient to induce Wnt signaling and produced pronounced tumors not seen with other oncogenic ß-catenin alleles. We identify pHi dynamics as a previously unrecognized regulator of ß-catenin stability, functioning in coincidence with phosphorylation.