Glycogen synthase kinase 3 drives thymocyte egress by suppressing β-catenin activation of Akt.

Abstract

Molecular pathways controlling emigration of mature thymocytes from thymus to the periphery remain incompletely understood. Here, we show that T cell–specific ablation of glycogen synthase kinase 3 (GSK3) led to severely impaired thymic egress. In the absence of GSK3, β-catenin accumulated in the cytoplasm, where it associated with and activated Akt, leading to phosphorylation and degradation of Foxo1 and downregulation of Klf2 and S1P₁ expression, thereby preventing emigration of thymocytes. A cytoplasmic membrane-localized β-catenin excluded from the nucleus promoted Akt activation, suggesting a new function of β-catenin independent of its role as a transcriptional activator. Furthermore, genetic ablation of β-catenin, retroviral expression of a dominant negative Akt mutant, and transgenic expression of a constitutively active Foxo1 restored emigration of GSK3-deficient thymocytes. Our findings establish an essential role for GSK3 in thymocyte egress and reveal a previously unidentified signaling function of β-catenin in the cytoplasm.