Regulated nuclear import of the STAT1 transcription factor by direct binding of importin‐α
Open accessAbstract
Signal transducers and activators of transcription (STATs) reside in a latent state in the cytoplasm of the cell, but accumulate in the nucleus in response to cytokines or growth factors. Localization in the nucleus occurs following STAT tyrosine phosphorylation and dimerization. In this report we demonstrate a direct interaction of importin-alpha5 with tyrosine-phosphorylated STAT1 dimers, and provide evidence that a nuclear localization signal (NLS) exists in an inactive state within a STAT1 monomer. A mutation in STAT1 leucine 407 (L407A) is characterized, which generates a protein that is accurately tyrosine phosphorylated in response to interferon, dimerizes and binds DNA, but does not localize to the nucleus. The import defect of STAT1(L407A) appears to be a consequence of the inability of this protein to be recognized by its import shuttling receptor. In addition, we demonstrate that STAT1 binding to specific target DNA effectively blocks importin-alpha5 binding. This result may play a role in localizing STAT1 to its destination in the nucleus, and in releasing importin-alpha5 from STAT1 for recycling back to the cytoplasm.
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A dimer-specific nuclear localization signal comprising residues 407-413 in the DNA-binding domain mediates binding of Stat1 dimers to importin α/β and subsequent nuclear import.
“Recently, we and others described an unusual dimer-specific nuclear localization signal (dsNLS) comprising residues 407-413 in the DNA-binding domain that mediates binding of Stat1 dimers to importin ␣/ and subsequent nuclear import (Fagerlund et al. 2002;McBride et al. 2002;Meyer et al. 2002a).”
From DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1 (2003) · cites this paper as McBride et al. 2002
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References 53 · Cited by 289
- Authors
- McBride, K. M., Banninger, G., McDonald, C., & Reich, N. C.
- Affiliations
- Stony Brook University (US)
- Corresponding author
- Reich, Nancy C.
- ORCID
- McBride, Kevin M.
- Venue
- The EMBO Journal
- Published
- 2002-04-01
- Volume
- 21
- Issue
- 7
- Pages
- 1754-1763
- ISSN
- 0261-4189 (ISSN-L)
- 1460-2075
- PMC
- PMC125956
- OpenAlex
- W2115597041
- Cited by
- 289
- References
- 53
- Citations by year
- 2026: 11 · 2025: 9 · 2024: 6 · 2023: 11 · 2022: 11 · 2021: 14 · 2020: 11 · 2019: 8 · 2018: 7 · 2017: 10 · 2016: 11 · 2015: 6 · 2014: 13 · 2013: 14 · 2012: 10
- FWCI
- 7.19
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- The EMBO Journal (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Cleveland Clinic
- Cleveland Clinic Foundation
- National Institutes of Health (RO1CA50773, PO1CA28146)
- National Cancer Institute (P01CA028146, P01CA28146, R01CA050773, R01CA50773)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Nuclear Structure and Function
- Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
- Life Sciences › Immunology and Microbiology › Immunology › interferon and immune responses
- Keywords
- STAT1, nuclear import, nuclear localization signal, tyrosine phosphorylation, interferon signaling, DNA binding, protein shuttling
- MeSH terms
- Animals, Binding Sites, Cell Nucleus, DNA, DNA-Binding Proteins, HeLa Cells, Humans, Phosphorylation, Recombinant Fusion Proteins, Tumor Cells, Cultured, Trans-Activators, Mutagenesis, Dimerization, Nuclear Localization Signals, Active Transport, Cell Nucleus, alpha Karyopherins, STAT1 Transcription Factor, Mice
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