Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling

Riccio, Amanda A.; McCauley, Michael; Langelier, Marie-France; Pascal, John M.

doi:10.1016/j.str.2016.06.022

Cited by 41 publications

(78 citation statements)

References 42 publications

(62 reference statements)

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“…We suggest that this can be explained by the severely increased amount of AXIN2 after G007-LK treatment, which induces the polymerization of degradasome components. Polymerization of AXIN1/2, APC and TNKS1/2 are thought to increase avidity for downstream signaling effectors and thus being a prerequisite for efficient β-catenin degradation [27–31]. Thus it seems that AXIN2 may be more important for switching off Wnt signaling, while AXIN1 may predominate in mediating the transition from Wnt off to Wnt on state by being recruited to signalosomes.…”

Section: Resultsmentioning

confidence: 99%

Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and β-Catenin Degradation

et al. 2017

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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.

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Section: Resultsmentioning

confidence: 99%

Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and β-Catenin Degradation

et al. 2017

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“…(A)]. Immediately upstream of this catalytic domain lies a SAM domain responsible for TNKSs polymerization . The extreme N‐terminal end harbors a histidine, serine, proline‐rich segment (a region lacking in tankyrase‐2), followed by a large ankyrin repeat domain composed of five conserved subdomains or ankyrin repeat clusters (ARCs) connected by conserved linkers.…”

Section: Introductionmentioning

confidence: 99%

Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

DaRosa¹,

Klevit²,

Xu³

2018

Protein Science

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Poly(ADP-ribosyl)ation (PARylation) catalyzed by the tankyrase enzymes (Tankyrase-1 and -2; a.k.a. PARP-5a and -5b) is involved in mitosis, telomere length regulation, GLUT-4 vesicle transport, and cell growth and differentiation. Together with the E3 ubiquitin ligase RNF146 (a.k.a. Iduna), tankyrases regulate the cellular levels of several important proteins including Axin, 3BP2, and angiomotins, which are key regulators of Wnt, Src and Hippo signaling, respectively. These tankyrase substrates are first PARylated and then ubiquitylated by RNF146, which is allosterically activated by binding to PAR polymer. Each tankyrase substrate is recognized by a tankyrase-binding motif (TBM). Here we show that RNF146 binds directly to tankyrases via motifs in its C-terminal region. Four of these RNF146 motifs represent novel, extended TBMs, that have one or two additional amino acids between the most conserved Arg and Gly residues. The individual RNF146 motifs display weak binding, but together mediate a strong multivalent interaction with the substrate-binding region of TNKS, forming a robust one-to-one complex. A crystal structure of the first RNF146 noncanonical TBM in complex with the second ankyrin repeat domain of TNKS shows how an extended motif can be accommodated in a peptide-binding groove on tankyrases. Overall, our work demonstrates the existence of a new class of extended TBMs that exist in previously uncharacterized tankyrase-binding proteins including those of IF4A1 and NELFE.

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“…Furthermore, additional tankyrase interactors in the Wnt/β‐catenin pathway, other than AXIN, are emerging (Croy et al, ). Structure–function studies are providing a detailed picture of the molecular mechanisms by which tankyrase controls Wnt/β‐catenin signalling and are revealing non‐catalytic scaffolding roles of tankyrase (Guettler et al, ; Morrone et al, ; DaRosa et al, , ; Eisemann et al, ; Mariotti et al, ; Riccio et al, ; Xu et al, ). Conserved functions of tankyrase in the Wnt/β‐catenin pathway are being increasingly appreciated from studies in Drosophila and human CRC cell lines (Lau et al, ; de la Roche et al, ; Yang et al, ; Wang et al, , ).…”

Section: Regulation Of Wnt/β‐catenin Signalling By Tankyrase‐dependenmentioning

confidence: 99%

“…Further studies are needed to explore this hypothesis. In the context of polymeric tankyrase, it appears equally likely that AXIN binds separate tankyrase molecules in the same tankyrase filament, with different implications for tankyrase conformation and potentially a further augmentation of cooperativity (Mariotti et al, ; Riccio et al, ).…”

Section: Tankyrase As a Scaffold In Wnt/β‐catenin Signalling – A Strumentioning

confidence: 99%

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

Mariotti

Pollock

Guettler

2017

British J Pharmacology

105

120

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The Wnt/β‐catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration‐limited pathway components and a wide range of post‐translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP‐ribosyl)ation (PARylation) and acetylation. Regulation of Wnt/β‐catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the β‐catenin destruction complex, and targets it for degradation, thereby fine‐tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt‐dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/β‐catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re‐tune Wnt/β‐catenin signalling in colorectal cancer cells.Linked ArticlesThis article is part of a themed section on WNT Signalling: Mechanisms and Therapeutic Opportunities. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v174.24/issuetoc

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Tankyrase Sterile α Motif Domain Polymerization Is Required for Its Role in Wnt Signaling

Cited by 41 publications

References 42 publications

Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and β-Catenin Degradation

Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and β-Catenin Degradation

Structural basis for tankyrase‐RNF146 interaction reveals noncanonical tankyrase‐binding motifs

Regulation of Wnt/β‐catenin signalling by tankyrase‐dependent poly(ADP‐ribosyl)ation and scaffolding

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