title: Differential Roles of AXIN1 and AXIN2 in Tankyrase Inhibitor-Induced Formation of Degradasomes and β-Catenin Degradation.
abstract: 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.
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, Oslo University Hospital, Oslo, Norway.|Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Tor Espen
authors.initials: TE
authors.lastname: Thorvaldsen
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, Oslo University Hospital, Oslo, Norway.|Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Nina Marie
authors.initials: NM
authors.lastname: Pedersen
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, Oslo University Hospital, Oslo, Norway.|Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Eva Maria
authors.identifier: http://orcid.org/0000-0002-5561-3344
authors.initials: EM
authors.lastname: Wenzel
authors.affiliation: Centre for Cancer Biomedicine, Faculty of Medicine, Oslo University Hospital, Oslo, Norway.|Department of Molecular Cell Biology, Institute for Cancer Research, Oslo University Hospital, Oslo, Norway.
authors.forename: Harald
authors.initials: H
authors.lastname: Stenmark
mesh_terms: D060466:Axin Protein / Q000502:physiology*; D015153:Blotting, Western; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000503:physiopathology; D022162:Cytoplasmic Vesicles / Q000502:physiology; D006801:Humans; D046988:Proteasome Endopeptidase Complex / Q000502:physiology; D059748:Proteolysis; D013450:Sulfones / Q000494:pharmacology; D038501:Tankyrases / Q000037:antagonists & inhibitors; D014230:Triazoles / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000502:physiology; D051176:beta Catenin / Q000378:metabolism*
chemical_list: C555451:AXIN1 protein, human; C491761:AXIN2 protein, human; D060466:Axin Protein; C582305:G007-LK; D013450:Sulfones; D014230:Triazoles; D051176:beta Catenin; D038501:Tankyrases; D046988:Proteasome Endopeptidase Complex