Wnt pathway activation by ADP-ribosylation.

Yang E, Tacchelly-Benites O, Wang Z, Randall MP, Tian A, Benchabane H, Freemantle S, Pikielny C, Tolwinski NS, Lee E, Ahmed Y
Nat Commun. 2016 7: 11430

PMID: 27138857 · PMCID: PMC4857404 · 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.

MeSH Terms (21)

Adenosine Diphosphate Ribose Amino Acid Sequence Animals Animals, Genetically Modified Axin Protein beta Catenin Cell Line, Tumor Drosophila melanogaster Drosophila Proteins Embryo, Nonmammalian Gene Expression Regulation, Developmental HEK293 Cells Humans Low Density Lipoprotein Receptor-Related Protein-6 Lymphocytes Molecular Sequence Data Proteolysis Sequence Alignment Tankyrases Wnt3A Protein Wnt Signaling Pathway

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