Inhibition of β‐catenin transactivation by IFNγ is regulated by Akt1 and 14.3.3z (650.1)

Abstract

The proinflammatory cytokine IFNg 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. B‐catenin activation has been classically associated with increased IEC proliferation. However, we have observed that IFNg inhibits IEC proliferation despite sustained activation of Akt/B‐catenin signaling. Here we show that inhibition of Akt/B‐catenin‐mediated cell proliferation by IFNg requires the formation of a protein complex containing phosphorylated B‐catenin 552 (pB‐cat552) and 14.3.3Z. We identify Akt1 as a bimodal switch that promotes or inhibits B‐catenin transcriptional activity in response to IFNg stimulation. We demonstrate that IFNg initially induces B‐catenin transactivation through Akt‐dependent c‐terminal phosphorylation of B‐catenin to promote its association with 14.3.3Z. Augmented B‐catenin transactivation leads to increased Akt1 protein and active Akt1 accumulates in the nucleus where it phosphorylates 14.3.3Z to induce relocalization of 14.3.3Z/B‐catenin from the nucleus thereby inhibiting B‐catenin transactivation and IEC proliferation. These results outline an unexpected dual function of Akt1 that suppresses IEC proliferation during intestinal inflammation.Grant Funding Source: Supported by NIH (CP and AN) and Conacyt (PN) grants.