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

Abstract

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

mTOR Senses Intracellular pH through Lysosome Dispersion from RHEB

“…Likewise, protonation of residues in talin increases its association with focal adhesions, slowing focal adhesion turnover and thereby motility at low pH . Similarly, histidine protonation plays an important role in regulating additional cancer‐relevant proteins involved in cytoskeleton regulation and signaling, such as β‐catenin and RasGRP1 . Metabolites themselves can also be influenced by acidification.…”

Intracellular pH controls Wnt signaling downstream of glycolysis in the vertebrate embryo

“…The pHi can control the protonation of specific histidines in proteins acting as pH sensors, leading to changes in the protein properties (3). In some epithelial cells, the pHi level can regulate β -catenin stability by controlling its binding to β -TrCP and hence its degradation (23). While acetylation of protein substrates such as histones is largely regulated by HATs and HDACs enzymes, non-enzymatic acetylation of proteins has also been demonstrated in many different cell types (24).…”

What is pH regulation, and why do cancer cells need it?

“…The first involves a re-modeling of pH sensitivity, which could be achieved through genetic mutations involving titratable residues, such as histidines [4,[24][25][26]. The protonation state of histidine changes dramatically over the expanded physiological range, bestowing proteins with exquisite pH-dependence [27][28][29]. A shift in the pH sensitivity curve may, for example, allow mutant proteins to remain active even at an abnormal level of pH [4].…”