AXIN2 promotes degradation of AXIN1 through tankyrase in colorectal cancer cells.
AXIN1
AXIN2
TNKS
Wnt pathway
colorectal cancer
Journal
The FEBS journal
ISSN: 1742-4658
Titre abrégé: FEBS J
Pays: England
ID NLM: 101229646
Informations de publication
Date de publication:
18 Jul 2024
18 Jul 2024
Historique:
revised:
12
06
2024
received:
09
04
2024
accepted:
05
07
2024
medline:
18
7
2024
pubmed:
18
7
2024
entrez:
18
7
2024
Statut:
aheadofprint
Résumé
AXIN1 and AXIN2 are homologous proteins that inhibit the Wnt/β-catenin signaling pathway, which is frequently hyperactive in colorectal cancer. Stabilization of AXIN1 and AXIN2 by inhibiting their degradation through tankyrase (TNKS) allows the attenuation of Wnt signaling in cancer, attracting interest for potential targeted therapy. Here, we found that knockout or knockdown of AXIN2 in colorectal cancer cells increased the protein stability of AXIN1. The increase in AXIN1 overcompensated for the loss of AXIN2 with respect to protein levels; however, functionally it did not because loss of AXIN2 activated the pathway. Moreover, AXIN2 was highly essential in the context of TNKS inhibition because TNKS-targeting small-molecule inhibitors completely failed to inhibit Wnt signaling and to stabilize AXIN1 in AXIN2 knockout cells. The increased AXIN1 protein stability and the impaired stabilization by TNKS inhibitors indicated disrupted TNKS-AXIN1 regulation in AXIN2 knockout cells. Concordantly, mechanistic studies revealed that co-expression of AXIN2 recruited TNKS to AXIN1 and stimulated TNKS-mediated degradation of transiently expressed AXIN1 wild-type and AXIN1 mutants with impaired TNKS binding. Taken together, our data suggest that AXIN2 promotes degradation of AXIN1 through TNKS in colorectal cancer cells by directly linking the two proteins, and these findings may be relevant for TNKS inhibition-based colorectal cancer therapies.
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : Wilhelm Sander-Stiftung
ID : 2018.017.2
Organisme : Deutsche Forschungsgemeinschaft
ID : BE 7055/2-1
Informations de copyright
© 2024 The Author(s). The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies.
Références
Stamos JL & Weis WI (2013) The beta‐catenin destruction complex. Cold Spring Harb Perspect Biol 5, a007898.
MacDonald BT & He X (2012) Frizzled and LRP5/6 receptors for Wnt/beta‐catenin signaling. Cold Spring Harb Perspect Biol 4, a007880.
Cadigan KM & Waterman ML (2012) TCF/LEFs and Wnt signaling in the nucleus. Cold Spring Harb Perspect Biol 4, a007906.
Cancer Genome Atlas N (2012) Comprehensive molecular characterization of human colon and rectal cancer. Nature 487, 330–337.
Behrens J, Jerchow BA, Wurtele M, Grimm J, Asbrand C, Wirtz R, Kuhl M, Wedlich D & Birchmeier W (1998) Functional interaction of an axin homolog, conductin, with beta‐catenin, APC, and GSK3beta. Science 280, 596–599.
Zeng L, Fagotto F, Zhang T, Hsu W, Vasicek TJ, Perry WL 3rd, Lee JJ, Tilghman SM, Gumbiner BM & Costantini F (1997) The mouse fused locus encodes axin, an inhibitor of the Wnt signaling pathway that regulates embryonic axis formation. Cell 90, 181–192.
Bernkopf DB, Hadjihannas MV & Behrens J (2015) Negative‐feedback regulation of the Wnt pathway by conductin/axin2 involves insensitivity to upstream signalling. J Cell Sci 128, 33–39.
Fiedler M, Mendoza‐Topaz C, Rutherford TJ, Mieszczanek J & Bienz M (2011) Dishevelled interacts with the DIX domain polymerization interface of Axin to interfere with its function in down‐regulating beta‐catenin. Proc Natl Acad Sci USA 108, 1937–1942.
Fagotto F, Jho E, Zeng L, Kurth T, Joos T, Kaufmann C & Costantini F (1999) Domains of axin involved in protein‐protein interactions, Wnt pathway inhibition, and intracellular localization. J Cell Biol 145, 741–756.
Bernkopf DB, Bruckner M, Hadjihannas MV & Behrens J (2019) An aggregon in conductin/axin2 regulates Wnt/beta‐catenin signaling and holds potential for cancer therapy. Nat Commun 10, 4251.
Lustig B, Jerchow B, Sachs M, Weiler S, Pietsch T, Karsten U, van de Wetering M, Clevers H, Schlag PM, Birchmeier W et al. (2002) Negative feedback loop of Wnt signaling through upregulation of conductin/axin2 in colorectal and liver tumors. Mol Cell Biol 22, 1184–1193.
Jho EH, Zhang T, Domon C, Joo CK, Freund JN & Costantini F (2002) Wnt/beta‐catenin/Tcf signaling induces the transcription of Axin2, a negative regulator of the signaling pathway. Mol Cell Biol 22, 1172–1183.
Leung JY, Kolligs FT, Wu R, Zhai Y, Kuick R, Hanash S, Cho KR & Fearon ER (2002) Activation of AXIN2 expression by beta‐catenin‐T cell factor. A feedback repressor pathway regulating Wnt signaling. J Biol Chem 277, 21657–21665.
Huang SM, Mishina YM, Liu S, Cheung A, Stegmeier F, Michaud GA, Charlat O, Wiellette E, Zhang Y, Wiessner S et al. (2009) Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461, 614–620.
Morrone S, Cheng Z, Moon RT, Cong F & Xu W (2012) Crystal structure of a Tankyrase–Axin complex and its implications for Axin turnover and Tankyrase substrate recruitment. Proc Natl Acad Sci USA 109, 1500–1505.
Kim DY, Kwon YJ, Seo WY, Kim UI, Ahn S, Choi SM, Bang HT, Kim K & Kim JS (2022) Tankyrase‐selective inhibitor STP1002 shows preclinical antitumour efficacy without on‐target toxicity in the gastrointestinal tract. Eur J Cancer 173, 41–51.
Leenders RGG, Brinch SA, Sowa ST, Amundsen‐Isaksen E, Galera‐Prat A, Murthy S, Aertssen S, Smits JN, Nieczypor P, Damen E et al. (2021) Development of a 1,2,4‐Triazole‐based Lead Tankyrase inhibitor: part II. J Med Chem 64, 17936–17949.
Thorvaldsen TE, Pedersen NM, Wenzel EM & Stenmark H (2017) Differential roles of AXIN1 and AXIN2 in Tankyrase inhibitor‐induced formation of degradasomes and beta‐catenin degradation. PLoS One 12, e0170508.
Klement K, Bruckner M & Bernkopf DB (2023) Phosphorylation of axin within biomolecular condensates counteracts its tankyrase‐mediated degradation. J Cell Sci 136, jcs261214.
Kinzler KW & Vogelstein B (1996) Lessons from hereditary colorectal cancer. Cell 87, 159–170.
Miete C, Solis GP, Koval A, Bruckner M, Katanaev VL, Behrens J & Bernkopf DB (2022) Galphai2‐induced conductin/axin2 condensates inhibit Wnt/beta‐catenin signaling and suppress cancer growth. Nat Commun 13, 674.
Ran FA, Hsu PD, Wright J, Agarwala V, Scott DA & Zhang F (2013) Genome engineering using the CRISPR‐Cas9 system. Nat Protoc 8, 2281–2308.