Complex regulatory interplay of γ‐catenin and β‐catenin in liver cells (59.10)

Abstract

β‐catenin, an adherens junction (AJ) component and key Wnt pathway effector, regulates numerous developmental processes, and its aberrant activation is observed in hepatocellular carcinoma (HCC). The β‐catenin homologue γ‐catenin (also known as Plakoglobin) is a constituent of desmosomes and adherens junctions and may participate in Wnt signaling in certain situations. We have reported hepatocyte‐specific β‐catenin knockout (KO) mice to lack any cell‐cell adhesion defects due to increased γ‐catenin especially at the AJs. To further elucidate the role and regulation of γ‐catenin‐β‐catenin relationship, we modulated these molecules in HCC cells. β‐Catenin knockdown (KD) in HCC cells led to increased γ‐catenin, which was associated with its increased serine/threonine phosphorylation. γ‐Catenin KD led to increased β‐catenin levels and transactivation. Overexpression of γ‐catenin led to β‐catenin downregulation, with increased Serine‐45 phosphorylation and increased GSK3β activity. Transfection of γ‐catenin plasmid did not change TopFlash reporter activity in Hep3B cells. In fact, levels of cyclin‐D1, a known β‐catenin target, decreased notably. Overexpression of γ‐catenin also decreased E‐cadherin protein levels. Thus, complex regulatory interplay between γ‐catenin and β‐catenin is observed, which may have important biological implications in hepatic pathobiology.