title: Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
abstract: The stability of the Wnt pathway transcription factor beta-catenin is tightly regulated by the multi-subunit destruction complex. Deregulated Wnt pathway activity has been implicated in many cancers, making this pathway an attractive target for anticancer therapies. However, the development of targeted Wnt pathway inhibitors has been hampered by the limited number of pathway components that are amenable to small molecule inhibition. Here, we used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin, the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, we discovered that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase 1 and tankyrase 2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway. Thus, our study provides new mechanistic insights into the regulation of axin protein homeostasis and presents new avenues for targeted Wnt pathway therapies.
authors.affiliation: Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
authors.forename: Shih-Min A
authors.initials: SM
authors.lastname: Huang
authors.forename: Yuji M
authors.initials: YM
authors.lastname: Mishina
authors.forename: Shanming
authors.initials: S
authors.lastname: Liu
authors.forename: Atwood
authors.initials: A
authors.lastname: Cheung
authors.forename: Frank
authors.initials: F
authors.lastname: Stegmeier
authors.forename: Gregory A
authors.initials: GA
authors.lastname: Michaud
authors.forename: Olga
authors.initials: O
authors.lastname: Charlat
authors.forename: Elizabeth
authors.initials: E
authors.lastname: Wiellette
authors.forename: Yue
authors.initials: Y
authors.lastname: Zhang
authors.forename: Stephanie
authors.initials: S
authors.lastname: Wiessner
authors.forename: Marc
authors.initials: M
authors.lastname: Hild
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Shi
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Wilson
authors.forename: Craig
authors.initials: C
authors.lastname: Mickanin
authors.forename: Vic
authors.initials: V
authors.lastname: Myer
authors.forename: Aleem
authors.initials: A
authors.lastname: Fazal
authors.forename: Ronald
authors.initials: R
authors.lastname: Tomlinson
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Serluca
authors.forename: Wenlin
authors.initials: W
authors.lastname: Shao
authors.forename: Hong
authors.initials: H
authors.lastname: Cheng
authors.forename: Michael
authors.initials: M
authors.lastname: Shultz
authors.forename: Christina
authors.initials: C
authors.lastname: Rau
authors.forename: Markus
authors.initials: M
authors.lastname: Schirle
authors.forename: Judith
authors.initials: J
authors.lastname: Schlegl
authors.forename: Sonja
authors.initials: S
authors.lastname: Ghidelli
authors.forename: Stephen
authors.initials: S
authors.lastname: Fawell
authors.forename: Chris
authors.initials: C
authors.lastname: Lu
authors.forename: Daniel
authors.initials: D
authors.lastname: Curtis
authors.forename: Marc W
authors.initials: MW
authors.lastname: Kirschner
authors.forename: Christoph
authors.initials: C
authors.lastname: Lengauer
authors.forename: Peter M
authors.initials: PM
authors.lastname: Finan
authors.forename: John A
authors.initials: JA
authors.lastname: Tallarico
authors.forename: Tewis
authors.initials: T
authors.lastname: Bouwmeester
authors.forename: Jeffery A
authors.initials: JA
authors.lastname: Porter
authors.forename: Andreas
authors.initials: A
authors.lastname: Bauer
authors.forename: Feng
authors.initials: F
authors.lastname: Cong
mesh_terms: D060466:Axin Protein; D002455:Cell Division / Q000187:drug effects; D002460:Cell Line; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000188:drug therapy / Q000378:metabolism; D006575:Heterocyclic Compounds, 3-Ring / Q000494:pharmacology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism; D011485:Protein Binding; D040901:Proteomics; D012097:Repressor Proteins / Q000737:chemistry / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D038501:Tankyrases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects; D025801:Ubiquitin / Q000378:metabolism; D054875:Ubiquitination; D051153:Wnt Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051176:beta Catenin / Q000037:antagonists & inhibitors / Q000378:metabolism
chemical_list: D060466:Axin Protein; D006575:Heterocyclic Compounds, 3-Ring; D012097:Repressor Proteins; D025801:Ubiquitin; D051153:Wnt Proteins; C544261:XAV939; D051176:beta Catenin; D038501:Tankyrases; D046988:Proteasome Endopeptidase Complex