IFNγ-induced suppression of β-catenin signaling: evidence for roles of Akt and 14.3.3ζ

The proinflammatory cytokine interferon gamma (IFN gamma) influences intestinal epithelial cell (IEC) homeostasis in a biphasic manner by acutely stimulating proliferation that is followed by sustained inhibition of proliferation despite continued mucosal injury. beta-Catenin activation has been classically associated with increased IEC proliferation. However, we observed that IFN gamma inhibits IEC proliferation despite sustained activation of Akt/beta-catenin signaling. Here we show that inhibition of Akt/beta-catenin-mediated cell proliferation by IFN gamma is associated with the formation of a protein complex containing phosphorylated beta-catenin 552 (p beta-cat552) and 14.3.3 zeta. Akt1 served as a bimodal switch that promotes or inhibits beta-catenin transactivation in response to IFN gamma stimulation. IFN gamma initially promotes beta-catenin transactivation through Akt-dependent C-terminal phosphorylation of beta-catenin to promote its association with 14.3.3 zeta. Augmented beta-catenin transactivation leads to increased Akt1 protein levels, and active Akt1 accumulates in the nucleus, where it phosphorylates 14.3.3 zeta to translocate 14.3.3 zeta/beta-catenin from the nucleus, thereby inhibiting beta-catenin transactivation and IEC proliferation. These results outline a dual function of Akt1 that suppresses IEC proliferation during intestinal inflammation.