Regulation of glycogen synthase kinase‐3beta by cell confluence

Abstract

Contact inhibition of cell growth is a fundamental property of normal cells to maintain tissue homeostasis. Loss of contact inhibition is associated with cellular transformation and enables cancer cells to grow in an uncontrolled fashion. E‐cadherin, a major component of the adherens junction, recruits beta‐catenin to the cell membrane and has been suggested to be responsible for the regulation of contact inhibition. E‐cadherin binding prevents beta‐catenin nuclear translocation and transactivation of genes that promote the cell cycle. Phosphorylation of beta‐catenin by casein kinase 1 and glycogen synthase kinase‐3beta (GSK‐3beta) leads to its ubiquitination and degradation. GSK‐3beta has been implicated in diverse cellular functions including cell division and apoptosis. However, it is unclear whether cell‐cell junctions regulate GSK‐3beta activity. Our data showed that the percentages of cells in S and G2/M phases of the cell cycle were increased in a variety of cells when cultured at low densities. Downregulation of GSK‐3beta activity by phosphorylation at serine 9 and dephosphorylation of its downstream target beta‐catenin were detected in non‐confluent cells, as compared to the cells in high density culture. Moreover, nuclear accumulation of GSK‐3beta was observed in non‐confluent cells. Taken together, our results suggest a role of cell‐cell junctions in regulating GSK‐3beta activity.