?-Catenin is a pH sensor with decreased stability at higher intracellular pH.

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

SUBMITTER: White KA 

PROVIDER: S-EPMC6219716 | biostudies-literature | 2018 Nov

REPOSITORIES: biostudies-literature