title: Akt Phosphorylates Wnt Coactivator and Chromatin Effector Pygo2 at Serine 48 to Antagonize Its Ubiquitin/Proteasome-mediated Degradation.
abstract: 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.
authors.affiliation: From the Department of Biological Chemistry, the State Key Laboratory of Molecular and Developmental Biology, Center for Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Qiuling
authors.initials: Q
authors.lastname: Li
authors.affiliation: the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Yuewei
authors.initials: Y
authors.lastname: Li
authors.affiliation: From the Department of Biological Chemistry.
authors.forename: Bingnan
authors.initials: B
authors.lastname: Gu
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697.
authors.forename: Lei
authors.initials: L
authors.lastname: Fang
authors.affiliation: the Department of Pathology and Laboratory Medicine, Weill Cornell Medical College, New York, New York 10065.
authors.forename: Pengbo
authors.initials: P
authors.lastname: Zhou
authors.affiliation: the State Key Laboratory of Molecular and Developmental Biology, Center for Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing 100101, China, and.
authors.forename: Shilai
authors.initials: S
authors.lastname: Bao
authors.affiliation: Department of Physiology and Biophysics, School of Medicine, University of California, Irvine, California 92697, lanhuang@uci.edu.
authors.forename: Lan
authors.initials: L
authors.lastname: Huang
authors.affiliation: From the Department of Biological Chemistry, xdai@uci.edu.
authors.forename: Xing
authors.initials: X
authors.lastname: Dai
mesh_terms: D000595:Amino Acid Sequence; D002467:Cell Nucleus / Q000378:metabolism; D002843:Chromatin / Q000378:metabolism*; D044842:Cullin Proteins / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D010766:Phosphorylation; D010768:Phosphoserine / Q000378:metabolism; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D011485:Protein Binding; D055550:Protein Stability; D059748:Proteolysis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D025801:Ubiquitin / Q000378:metabolism*; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism; D054875:Ubiquitination; D015854:Up-Regulation; D051153:Wnt Proteins / Q000378:metabolism*
chemical_list: D002843:Chromatin; D044842:Cullin Proteins; C091435:DDB1 protein, human; D004268:DNA-Binding Proteins; D036341:Intercellular Signaling Peptides and Proteins; D047908:Intracellular Signaling Peptides and Proteins; C453401:PYGO2 protein, human; D025801:Ubiquitin; D051153:Wnt Proteins; D010768:Phosphoserine; D044767:Ubiquitin-Protein Ligases; D051057:Proto-Oncogene Proteins c-akt; D046988:Proteasome Endopeptidase Complex
keywords: Akt; Cul4; DDB1; E3 ubiquitin ligase; Pygo2; Wnt signaling; phosphorylation; ubiquitin ligase; ubiquitylation (ubiquitination)