Fig. 8. GSK3 regulation of thymocyte egress: A model.

The S1P gradient provides a driving force for the egress of mature thymocytes into the bloodstream. A Foxo1-Klf2 axis controls the expression of S1P receptor S1P₁ on mature thymocytes. Constitutive expression and activity of GSK3 in WT thymocytes are required for suppressing tonic Akt signaling by phosphorylating β-catenin, leading to its degradation. In the absence of GSK3, β-catenin accumulates in the cytoplasm, where it promotes Akt activation by decreasing the association of Akt with its phosphatases, PHLPP2 and PP2A, resulting in Foxo1 phosphorylation and degradation, diminished Klf2 and S1P₁ expression, and impaired thymocyte egress.