Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.
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.
Huang
Shih-Min A
SM
Novartis Institutes for Biomedical Research, 250 Massachusetts Avenue, Cambridge, Massachusetts 02139, USA.
Mishina
Yuji M
YM
Liu
Shanming
S
Cheung
Atwood
A
Stegmeier
Frank
F
Michaud
Gregory A
GA
Charlat
Olga
O
Wiellette
Elizabeth
E
Zhang
Yue
Y
Wiessner
Stephanie
S
Hild
Marc
M
Shi
Xiaoying
X
Wilson
Christopher J
CJ
Mickanin
Craig
C
Myer
Vic
V
Fazal
Aleem
A
Tomlinson
Ronald
R
Serluca
Fabrizio
F
Shao
Wenlin
W
Cheng
Hong
H
Shultz
Michael
M
Rau
Christina
C
Schirle
Markus
M
Schlegl
Judith
J
Ghidelli
Sonja
S
Fawell
Stephen
S
Lu
Chris
C
Curtis
Daniel
D
Kirschner
Marc W
MW
Lengauer
Christoph
C
Finan
Peter M
PM
Tallarico
John A
JA
Bouwmeester
Tewis
T
Porter
Jeffery A
JA
Bauer
Andreas
A
Cong
Feng
F
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
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