Wnt pathway activation by ADP-ribosylation

Nat Commun. 2016 May 3;7:11430. doi: 10.1038/ncomms11430.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Adenosine Diphosphate Ribose / metabolism*
  • Amino Acid Sequence
  • Animals
  • Animals, Genetically Modified
  • Axin Protein / genetics*
  • Axin Protein / metabolism
  • Cell Line, Tumor
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / embryology
  • Drosophila melanogaster / genetics*
  • Drosophila melanogaster / metabolism
  • Embryo, Nonmammalian
  • Gene Expression Regulation, Developmental
  • HEK293 Cells
  • Humans
  • 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
  • Proteolysis
  • Sequence Alignment
  • Tankyrases / genetics
  • Tankyrases / metabolism
  • Wnt Signaling Pathway / drug effects*
  • Wnt3A Protein / genetics*
  • Wnt3A Protein / metabolism
  • Wnt3A Protein / pharmacology
  • beta Catenin / genetics
  • beta Catenin / metabolism

Substances

  • Axin Protein
  • Axn protein, Drosophila
  • CTNNB1 protein, human
  • Drosophila Proteins
  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Wnt3A Protein
  • beta Catenin
  • Adenosine Diphosphate Ribose
  • Tankyrases
  • TNKS protein, human