Loss of β‐catenin in hepatocyte‐specific knockouts is compensated by γ‐catenin at the adherens junctions

β‐Catenin signaling is important in liver homeostasis. We have previously reported the creation of hepatocyte‐specific β‐catenin knockout (KO) mice that lack any overt phenotype. Here, we examined the effect of β‐catenin loss on the adherens junction (AJ), where it normally links E‐cadherin to the actin cytoskeleton. We confirmed the loss of β‐catenin in the epithelial compartment of the liver in the KOs with no β‐catenin observed associating with E‐cadherin. We identify an increase in total γ‐catenin (plakoglobin) protein in KO over wild‐type (WT) littermate livers. In fact, higher γ‐catenin protein expression was evident upon β‐catenin knockdown in human hepatoma cell lines as well. We next show that the compensatory increase in γ‐catenin expression in the KO livers leads to sustained cadherin‐actin assembly albeit it is retained by γ‐catenin in lieu of β‐catenin. Also, γ‐catenin increase in the KOs is not due to changes in JUP gene expression, but appears to be post‐translational as indicated by increased serine/threonine phosphorylation of γ‐catenin in KO livers. γ‐Catenin was detected at very low levels in the nuclei in both KO and WT livers in contrast to β‐catenin, which did show a nuclear presence in WT livers. Also, KO livers lack expression of β‐catenin transcriptional targets such as glutamine synthetase. γ‐Catenin was also not detected in the hepatocyte nuclei of regenerating KO livers when peak proliferation is ongoing at 72hrs. Thus, β‐catenin loss is adequately compensated by γ‐catenin at the AJ; however, the functions of β‐catenin as a part of the Wnt pathway remain unfulfilled by γ‐catenin especially at baseline and during liver regeneration.