Journal of Biological Chemistry
Volume 290, Issue 35, 28 August 2015, Pages 21553-21567
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Signal Transduction
Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation*

https://doi.org/10.1074/jbc.M115.639419Get rights and content
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Pygopus 2 (Pygo2/PYGO2) is an evolutionarily conserved coactivator and chromatin effector in the Wnt/β-catenin signaling pathway that regulates cell growth and differentiation in various normal and malignant tissues. Although PYGO2 is highly overexpressed in a number of human cancers, the molecular mechanism underlying its deregulation is largely unknown. Here we report that Pygo2 protein is degraded through the ubiquitin/proteasome pathway and is posttranslationally stabilized through phosphorylation by activated phosphatidylinositol 3-kinase/Akt signaling. Specifically, Pygo2 is stabilized upon inhibition of the proteasome, and its intracellular level is regulated by Cullin 4 (Cul4) and DNA damage-binding protein 1 (DDB1), components of the Cul4-DDB1 E3 ubiquitin ligase complex. Furthermore, Pygo2 is phosphorylated at multiple residues, and Akt-mediated phosphorylation at serine 48 leads to its decreased ubiquitylation and increased stability. Finally, we provide evidence that Akt and its upstream growth factors act in parallel with Wnt to stabilize Pygo2. Taken together, our findings highlight chromatin regulator Pygo2 as a common node downstream of oncogenic Wnt and Akt signaling pathways and underscore posttranslational modification, particularly phosphorylation and ubiquitylation, as a significant mode of regulation of Pygo2 protein expression.

E3 ubiquitin ligase
phosphorylation
ubiquitin ligase
ubiquitylation (ubiquitination)
Wnt signaling
Akt
Cul4
DDB1
Pygo2

Cited by (0)

R01-GM083089R21CA161807R01GM074830National Institutes of Health

*

This work was supported, in whole or in part, by National Institutes of Health Grants R01-GM083089 (to X. D.) and R21CA161807 and R01GM074830 (to L. H.). This work was also supported by Susan G. Komen Grant KG110897 (to X. D.). The authors declare that they have no conflicts of interest with the contents of this article.

1

Supported by California Breast Cancer Research Program Postdoctoral Fellowship 14FB-0129.