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Wnt pathway activation by ADP-ribosylation

Author

Listed:
  • Eungi Yang

    (Geisel School of Medicine at Dartmouth College)

  • Ofelia Tacchelly-Benites

    (Geisel School of Medicine at Dartmouth College)

  • Zhenghan Wang

    (Geisel School of Medicine at Dartmouth College)

  • Michael P. Randall

    (Geisel School of Medicine at Dartmouth College)

  • Ai Tian

    (Geisel School of Medicine at Dartmouth College)

  • Hassina Benchabane

    (Geisel School of Medicine at Dartmouth College)

  • Sarah Freemantle

    (Geisel School of Medicine at Dartmouth College)

  • Claudio Pikielny

    (Geisel School of Medicine at Dartmouth College)

  • Nicholas S. Tolwinski

    (Yale-NUS College, National University of Singapore)

  • Ethan Lee

    (Vanderbilt Ingram Cancer Center, and Vanderbilt Institute of Chemical Biology)

  • Yashi Ahmed

    (Geisel School of Medicine at Dartmouth College)

Abstract

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.

Suggested Citation

  • Eungi Yang & Ofelia Tacchelly-Benites & Zhenghan Wang & Michael P. Randall & Ai Tian & Hassina Benchabane & Sarah Freemantle & Claudio Pikielny & Nicholas S. Tolwinski & Ethan Lee & Yashi Ahmed, 2016. "Wnt pathway activation by ADP-ribosylation," Nature Communications, Nature, vol. 7(1), pages 1-14, September.
    • Handle: RePEc:nat:natcom:v:7:y:2016:i:1:d:10.1038_ncomms11430
    DOI: 10.1038/ncomms11430
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