IFNγ-induced suppression of β-catenin signaling: evidence for roles of Akt and 14.3.3ζ.
Bottom Line: Akt1 served as a bimodal switch that promotes or inhibits β-catenin transactivation in response to IFNγ stimulation.IFNγ initially promotes β-catenin transactivation through Akt-dependent C-terminal phosphorylation of β-catenin to promote its association with 14.3.3ζ.These results outline a dual function of Akt1 that suppresses IEC proliferation during intestinal inflammation.
Affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico.Show MeSH
Related in: MedlinePlus
Mentions: The role of Akt in regulation of β-catenin signaling is incompletely understood and controversial. From the findings in this study and others (Dihlmann et al., 2005; He et al., 2007; Li et al., 2008), it is likely that controversy over the role of Akt is related, in part, to type and duration of stimulus and cellular concentrations of Akt. Through analyses of the response of IECs to IFNγ treatment, we were able to demonstrate that Akt1 controls activation and inhibition of β-catenin signaling downstream of IFNγ and propose a hypothetical model in which Akt1 controls the fate of β-catenin through regulation of cellular localization of the complex 14.3.3ζ/pβ-cat552 (Figure 6). The model we propose predicts that PI3K activation by IFNγ (Kaur et al., 2008) results in the activation of Akt1. Active Akt phosphorylates β-catenin at serine 552. Such posttranslational events facilitate interaction of β-catenin with 14.3.3ζ, thereby promoting β-catenin stabilization and transactivation (Figure 6, left; Tian et al., 2004). As a consequence of this process, Akt1 protein levels increase. Elevated levels of Akt1 result in enrichment of pAkt308 within the nucleus, enhances phosphorylation of 14.3.3ζ at serine 58 by Akt (Powell et al., 2002), and its subsequent relocalization from nucleus to cytosol, where the molecules accumulate (Figure 3, D and E; Tian et al., 2004; He et al., 2007). It is therefore likely that the foregoing mechanism is responsible for the expulsion of 14.3.3ζ and pβ-cat552 from the nuclear compartment, resulting in inhibition of β-catenin transactivation and inhibition of IEC proliferation (Figure 6, right).
Affiliation: Epithelial Pathobiology and Mucosal Inflammation Research Unit, Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Instituto Politécnico Nacional, 07360 Mexico City, Mexico.