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.
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Eungi
authors.initials: E
authors.lastname: Yang
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Ofelia
authors.initials: O
authors.lastname: Tacchelly-Benites
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Zhenghan
authors.initials: Z
authors.lastname: Wang
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Michael P
authors.initials: MP
authors.lastname: Randall
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Ai
authors.initials: A
authors.lastname: Tian
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Hassina
authors.initials: H
authors.lastname: Benchabane
authors.affiliation: Department of Pharmacology and Toxicology, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Sarah
authors.initials: S
authors.lastname: Freemantle
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Claudio
authors.initials: C
authors.lastname: Pikielny
authors.affiliation: Department of Biological Sciences, Yale-NUS College, National University of Singapore, Singapore 138615, Singapore.
authors.forename: Nicholas S
authors.initials: NS
authors.lastname: Tolwinski
authors.affiliation: Department of Cell and Developmental Biology, Vanderbilt Ingram Cancer Center, and Vanderbilt Institute of Chemical Biology, Nashville, Tennessee 37232, USA.
authors.forename: Ethan
authors.initials: E
authors.lastname: Lee
authors.affiliation: Department of Genetics and the Norris Cotton Cancer Center, Geisel School of Medicine at Dartmouth College, Hanover, New Hampshire 03755, USA.
authors.forename: Yashi
authors.initials: Y
authors.lastname: Ahmed
mesh_terms: D000246:Adenosine Diphosphate Ribose / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D030801:Animals, Genetically Modified; D060466:Axin Protein / Q000235:genetics* / Q000378:metabolism; D045744:Cell Line, Tumor; D029721:Drosophila Proteins / Q000235:genetics* / Q000378:metabolism; D004331:Drosophila melanogaster / Q000196:embryology / Q000235:genetics* / Q000378:metabolism; D004625:Embryo, Nonmammalian; D018507:Gene Expression Regulation, Developmental; D057809:HEK293 Cells; D006801:Humans; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D008969:Molecular Sequence Data; D059748:Proteolysis; D016415:Sequence Alignment; D038501:Tankyrases / Q000235:genetics / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000187:drug effects*; D060509:Wnt3A Protein / Q000235:genetics* / Q000378:metabolism / Q000494:pharmacology; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D000246:Adenosine Diphosphate Ribose; D060466:Axin Protein; D029721:Drosophila Proteins; D060488:Low Density Lipoprotein Receptor-Related Protein-6; D038501:Tankyrases; D060509:Wnt3A Protein; D051176:beta Catenin; C118000:Axn protein, Drosophila; C495270:CTNNB1 protein, human; C555475:LRP6 protein, human; C418109:TNKS protein, human