Date Published: January 20, 2017
Publisher: Public Library of Science
Author(s): Tor Espen Thorvaldsen, Nina Marie Pedersen, Eva Maria Wenzel, Harald Stenmark, Masaru Katoh.
Inhibition of the tankyrase enzymes (TNKS1 and TNKS2) has recently been shown to induce highly dynamic assemblies of β-catenin destruction complex components known as degradasomes, which promote degradation of β-catenin and reduced Wnt signaling activity in colorectal cancer cells. AXIN1 and AXIN2/Conductin, the rate-limiting factors for the stability and function of endogenous destruction complexes, are stabilized upon TNKS inhibition due to abrogated degradation of AXIN by the proteasome. Since the role of AXIN1 versus AXIN2 as scaffolding proteins in the Wnt signaling pathway still remains incompletely understood, we sought to elucidate their relative contribution in the formation of degradasomes, as these protein assemblies most likely represent the morphological and functional correlates of endogenous β-catenin destruction complexes. In SW480 colorectal cancer cells treated with the tankyrase inhibitor (TNKSi) G007-LK we found that AXIN1 was not required for degradasome formation. In contrast, the formation of degradasomes as well as their capacity to degrade β-catenin were considerably impaired in G007-LK-treated cells depleted of AXIN2. These findings give novel insights into differential functional roles of AXIN1 versus AXIN2 in the β-catenin destruction complex.
The Wnt signaling pathway orchestrates multiple developmental and adult homeostatic processes, whereas aberrant activation of the pathway underlies numerous human diseases such as cancer . β-catenin, the key mediator of Wnt signaling output , is earmarked for proteasomal degradation by the so-called β-catenin destruction complex, which consists of the structural proteins adenomatous polyposis coli (APC) and axis inhibition protein 1 and 2 (AXIN1/2), and the kinases casein kinase 1α (CK1α) and glycogen synthase kinase 3 (GSK3) . This signal-limiting complex is compromised in the majority of colorectal cancers due to mutations in the APC gene . Recently, the poly-ADP-ribosyltransferases tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) were implicated as positive regulators of Wnt signaling by transferring ADP-ribose moieties onto AXIN, the rate-limiting factor for destruction complex stability, thereby marking it for degradation by the ubiquitin-proteasome system [5, 6]. Consequently, tankyrase inhibitors (TNKSi) have emerged as promising new cancer therapeutics that stabilize AXIN and reduce Wnt signaling output . Intriguingly, several studies have reported the formation of distinct cytoplasmic puncta upon treatment with TNKSi [8–10]. These protein assemblies, referred to as degradasomes, contain destruction complex components and most likely represent the morphological and functional correlates of endogenous destruction complexes.