Wnt pathway activation by ADP-ribosylation

• Published in: Nature communications Vol. 7; no. 1; pp. 11430 - 14
• Main Authors: Yang, Eungi, Tacchelly-Benites, Ofelia, Wang, Zhenghan, Randall, Michael P, Tian, Ai, Benchabane, Hassina, Freemantle, Sarah, Pikielny, Claudio, Tolwinski, Nicholas S, Lee, Ethan, Ahmed, Yashi
• Format: Journal Article
• Language: English
• Published: England Nature Publishing Group 03.05.2016; Nature Portfolio
• Subjects: Adenosine Diphosphate Ribose - metabolism; Amino Acid Sequence; Animals; Animals, Genetically Modified; Axin Protein - genetics; Axin Protein - metabolism; beta Catenin - genetics; beta Catenin - metabolism; Cancer; Cell Line, Tumor; Drosophila melanogaster - embryology; Drosophila melanogaster - genetics; Drosophila melanogaster - metabolism; Drosophila Proteins - genetics; Drosophila Proteins - metabolism; Embryo, Nonmammalian; Gene Expression Regulation, Developmental; HEK293 Cells; Humans; Insects; Kinases; Low Density Lipoprotein Receptor-Related Protein-6 - genetics; Low Density Lipoprotein Receptor-Related Protein-6 - metabolism; Lymphocytes - cytology; Lymphocytes - drug effects; Lymphocytes - metabolism; Molecular Sequence Data; Phosphorylation; Physiology; Proteins; Proteolysis; Sequence Alignment; Signal transduction; Tankyrases - genetics; Tankyrases - metabolism; Wnt Signaling Pathway - drug effects; Wnt3A Protein - genetics; Wnt3A Protein - metabolism; Wnt3A Protein - pharmacology; United States > US; Singapore; New Hampshire
• ISSN: 2041-1723; 2041-1723
• DOI: 10.1038/ncomms11430

Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of the scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse the early effects of Wnt on Axin and find that the ADP-ribose polymerase Tankyrase (Tnks)--known to target Axin for proteolysis-regulates Axin's rapid transition following Wnt stimulation. We demonstrate that the pool of ADP-ribosylated Axin, which is degraded under basal conditions, increases immediately following Wnt stimulation in both Drosophila and human cells. ADP-ribosylation of Axin enhances its interaction with the Wnt co-receptor LRP6, an essential step in signalosome assembly. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling not only by increasing destruction complex activity, but also by impeding signalosome assembly.