Wnt pathway activation by ADP-ribosylation

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

doi:10.1038/ncomms11430

Wnt pathway activation by ADP-ribosylation

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

Research output: Contribution to journal › Article › peer-review

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.

Original language	English (US)
Article number	11430
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms11430
State	Published - May 3 2016
Externally published	Yes

ASJC Scopus subject areas

Chemistry(all)
Biochemistry, Genetics and Molecular Biology(all)
Physics and Astronomy(all)

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10.1038/ncomms11430

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@article{fe61407bbaa742ef9936261e56d5cfcf,

title = "Wnt pathway activation by ADP-ribosylation",

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.",

author = "Eungi Yang and Ofelia Tacchelly-Benites and Zhenghan Wang and Randall, {Michael P.} and Ai Tian and Hassina Benchabane and Sarah Freemantle and Claudio Pikielny and Tolwinski, {Nicholas S.} and Ethan Lee and Yashi Ahmed",

note = "Funding Information: We thank J. Cho, G. Deshpande, S. Ogden and E. Wieschaus for comments on the manuscript, K. Beckett, J. Byun, F. Cong, Y. Han, S. Kim, A. Lavanway, B. MacDonald and S. Ogden for technical advice, the investigators listed in Methods for generously sharing reagents, and V. Marlar for technical assistance. This work was funded by grants from the NIH (RO1CA105038 to Y.A., R01GM081635 and R01GM103926 to E.L., P40OD018537 to the Bloomington Drosophila Stock Center), the Emerald Foundation (to Y.A.), the Norris Cotton Cancer Center (to Y.A. and S.F.), the Academic Research Fund (MOE2014-T2-2-039 to NT) and the National Science Foundation (DBI-1039423 for purchase of a Nikon A1RSi confocal microscope). Publisher Copyright: {\textcopyright} 2016, Nature Publishing Group. All rights reserved.",

year = "2016",

month = may,

day = "3",

doi = "10.1038/ncomms11430",

language = "English (US)",

volume = "7",

journal = "Nature communications",

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T1 - Wnt pathway activation by ADP-ribosylation

AU - Yang, Eungi

AU - Tacchelly-Benites, Ofelia

AU - Wang, Zhenghan

AU - Randall, Michael P.

AU - Tian, Ai

AU - Benchabane, Hassina

AU - Freemantle, Sarah

AU - Pikielny, Claudio

AU - Tolwinski, Nicholas S.

AU - Lee, Ethan

AU - Ahmed, Yashi

N1 - Funding Information: We thank J. Cho, G. Deshpande, S. Ogden and E. Wieschaus for comments on the manuscript, K. Beckett, J. Byun, F. Cong, Y. Han, S. Kim, A. Lavanway, B. MacDonald and S. Ogden for technical advice, the investigators listed in Methods for generously sharing reagents, and V. Marlar for technical assistance. This work was funded by grants from the NIH (RO1CA105038 to Y.A., R01GM081635 and R01GM103926 to E.L., P40OD018537 to the Bloomington Drosophila Stock Center), the Emerald Foundation (to Y.A.), the Norris Cotton Cancer Center (to Y.A. and S.F.), the Academic Research Fund (MOE2014-T2-2-039 to NT) and the National Science Foundation (DBI-1039423 for purchase of a Nikon A1RSi confocal microscope). Publisher Copyright: © 2016, Nature Publishing Group. All rights reserved.

PY - 2016/5/3

Y1 - 2016/5/3

N2 - 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.

AB - 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.

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JO - Nature communications

JF - Nature communications

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ER -

Wnt pathway activation by ADP-ribosylation

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