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.

Leishmania donovani inhibits macrophage apoptosis and pro-inflammatory response through AKT-mediated regulation of β-catenin and FOXO-1

“…Error bars represent mean ± S.D., n = 3. NS, non-significant, **Po0.01,***Po0.001; Student's t-test inhibitor of β-catenin 25 or transiently transected with β-catenin siRNA and subjected to measurement of NF-κB luciferase activity. Significant increase in NF-κB reporter activity was observed in XAV939-treated and β-catenin-silenced infected cells (1.7-and 1.8-fold increase as compared with infected, Po0.01; Figure 3f).…”

Canonical and noncanonical Wnt signaling in neural stem/progenitor cells

“…It is therefore not surprising that so much effort has gone into the development of new drugs based on our knowledge of Wnt signaling to treat disease. Among the commercially available drugs that have been developed to manipulate Wnt signaling are IWP-2 and Wnt-C59, potent porcupine inhibitors that block Wnt secretion [13,14], IWR-1 and XAV939, which are tankyrase inhibitors that stabilize Axin and thereby inhibiting canonical Wnt signaling [13,15], CHIR99021 (CHIR), a GSK-3 inhibitor that activates Wnt signaling [16], and iCRT-14, which inhibits the β-catenin/TCF complex [17]. These inhibitors, as well as several others not mentioned here, have been important for driving progress of research in this field, and the development of possible therapies for Wnt-related diseases.…”

Myelin Regeneration in Multiple Sclerosis: Targeting Endogenous Stem Cells

“…As a specific example, several cancers, including the majority of colon adenocarcinomas, arise due to gain-offunction mutations in the canonical Wnt signaling pathway. Pharmacological inhibitors of Wnt pathway are being actively developed in cancer medicine and it is possible that these may also find a role in enhancing remyelination by inhibiting Wnt signaling in CNS precursors and normalizing the kinetics of myelin regeneration [81,82].…”