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

The DOI matches its Crossref record; 60 of the 60 references it cites were found in a registry or an index.

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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Metadata

Authors
Fagotto, F., Glück, U., & Gumbiner, B. M.
Affiliations
Memorial Sloan Kettering Cancer Center (US)
Corresponding author
Gumbiner, Barry M.
ORCID
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
Licence
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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