Cited by 434Wnt/β-catenin signaling in development and cancerNuclear Structure and FunctionDrug Transport and Resistance Mechanisms

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Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of β-catenin

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Fagotto, François, Glück, Ursula, Gumbiner, Barry M.·1998·Current Biology

DOI 10.1016/s0960-9822(98)70082-x

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Abstract

Background Control of the nuclear localization of specific proteins is an important mechanism for regulating many signal transduction pathways. Upon activation of the Wnt signaling pathway, beta-catenin localizes into the nucleus and interacts with TCF/LEF-1 (T-cell factor/lymphocyte enhancer factor-1) transcription factors, triggering activation of downstream genes. The role of regulated nuclear localization in beta-catenin signaling is still unclear. Beta-catenin has no nuclear localization sequence (NLS). Although it has been reported that beta-catenin can piggyback into the nucleus by binding to TCF/LEF-1, there is evidence that its import is independent of TCF/LEF-1 in vivo. Therefore, the mechanism for beta-catenin nuclear localization remains to be established.Results We have analyzed beta-catenin nuclear import in an in vitro assay using permeabilized cells. Beta-catenin docks specifically onto the nuclear envelope in the absence of other cytosolic factors. Docking is not inhibited by an NLS peptide and does not require importins/karyopherins, the receptors for classical NLS substrates. Rather, docking is specifically competed by importin-beta/beta-karyopherin, indicating that beta-catenin and importin-beta/beta-karyopherin both interact with common nuclear pore components. Nuclear translocation of beta-catenin is energy dependent and is inhibited by nonhydrolyzable GTP analogs and by a dominant-negative mutant form of the Ran GTPase. Cytosol preparations contain inhibitory activities for beta-catenin import that are distinct from the competition by importin-beta/beta-karyopherin and may be involved in the physiological regulation of the pathway.Conclusions Beta-catenin is imported into the nucleus by binding directly to the nuclear pore machinery, similar to importin-beta/beta-karyopherin or other importin-beta-like import factors, such as transportin. These findings provide an explanation for how beta-catenin localizes to the nucleus without an NLS and independently of its interaction with TCF/LEF-1. This is a new and unusual mechanism for the nuclear import of a signal transduction protein. The lack of beta-catenin import activity in the presence of normal cytosol suggests that its import may be regulated by upstream events in the Wnt signaling pathway.

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Authors: Fagotto, F., Glück, U., & Gumbiner, B. M.
Affiliations: Memorial Sloan Kettering Cancer Center (US)
Corresponding author: Gumbiner, Barry M.
ORCID: Fagotto, François
Gumbiner, Barry M.
Venue: Current Biology
Publisher: Elsevier BV
Published: 1998-02
Volume: 8
Issue: 4
Pages: 181-190
ISSN: 0960-9822 (ISSN-L)
DOI: 10.1016/s0960-9822(98)70082-x
OpenAlex: W1993496373
Cited by: 434
References: 60
Citations by year: 2026: 4 · 2025: 7 · 2024: 8 · 2023: 6 · 2022: 11 · 2021: 11 · 2020: 6 · 2019: 7 · 2018: 11 · 2017: 13 · 2016: 10 · 2015: 16 · 2014: 15 · 2013: 12 · 2012: 14
FWCI: 13.79
Type: journal article
Language: en
Open access: bronze
doi.org
Licence: www.elsevier.com/tdm/userlicense/1.0/ (tdm)
www.elsevier.com/open-access/userlicense/1.0/ (vor, 5645 d)
Locations: Current Biology (publishedVersion)
PubMed (publishedVersion)
Funders: National Institutes of Health
National Cancer Institute (P30CA008748)
National Institute of General Medical Sciences (GM37432)
Topics: Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Wnt/β-catenin signaling in development and cancer
Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
Health Sciences › Medicine › Oncology › Drug Transport and Resistance Mechanisms
Keywords: β-catenin, nuclear import, Wnt signaling, nuclear localization signal, importin beta, nuclear pore complex, Ran GTPase, signal transduction regulation
MeSH terms: Animals, Binding, Competitive, Biological Transport, Cell Nucleus, Cytoskeletal Proteins, Cytosol, Nuclear Proteins, Recombinant Proteins, Xenopus, Trans-Activators, Nuclear Localization Signals, Karyopherins, alpha Karyopherins, Xenopus Proteins, beta Catenin

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Nuclear localization signal-independent and importin/karyopherin-independent nuclear import of β-catenin

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