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  • Review Article
  • Published:

Tracking STAT nuclear traffic

Nature Reviews Immunology volume 6, pages 602–612 (2006)Cite this article

Key Points

  • The signal transducer and activator of transcription (STAT) transcription factors are activated by direct tyrosine phosphorylation in response to cytokines, growth factors and other hormones. Tyrosine phosphorylation promotes the formation of STAT dimers that can bind specific DNA targets.

  • Passage of large proteins between cytoplasmic and nuclear compartments occurs through nuclear pore complexes and is regulated by interaction with transporter proteins of the karyopherin-β family.

  • Individual STAT proteins have diversified with distinct nuclear trafficking regulation. Cellular localization of a particular STAT is dependent or independent of tyrosine phosphorylation.

  • Cellular localization of STAT1 is integrated with its ability to bind DNA. The nuclear localization and nuclear-export signals of STAT1 have co-evolved with the DNA-binding domain.

  • The regulation of STAT1 nuclear trafficking is conditional based on its state of tyrosine phosphorylation. A specific member of the importin-α family of adaptor molecules, importin-α5, recognizes a conditional nuclear-localization signal of the STAT1 phosphorylated dimer.

  • STAT2 is distinct among the STATs in that it constitutively interacts with the transcription factor interferon-regulatory factor 9 (IRF9). The constitutive nuclear-localization signal of IRF9 is responsible for nuclear localization of the unphosphorylated STAT2–IRF9 complex.

  • STAT2 has a nuclear-export signal located in its carboxyl terminus that is responsible for export of the unphosphorylated or phosphorylated STAT2 protein.

  • STAT3 is imported to the nucleus independent of tyrosine phosphorylation and dependent on recognition by the importin-α3 adaptor. The constitutive nuclear-localization signal of STAT3 is located in the coiled-coil domain, a distance from the DNA-binding domain.

  • Individual STATs have evolved distinct nuclear trafficking properties, and these distinguishing features may reflect their physiological roles. Understanding the molecular aspects that regulate their nuclear trafficking may provide an avenue to promote or inhibit STAT function.

Abstract

Accurate cellular localization is crucial for the effective function of most signalling molecules and nuclear translocation is central to the function of transcription factors. The passage of large molecules between the cytoplasm and nucleus is restricted, and this restriction affords a mechanism to regulate transcription by controlling the access of transcription factors to the nucleus. In this Review, we focus on the signal transducer and activator of transcription (STAT) family of transcription factors. The regulation of the nuclear trafficking of STAT-family members is diverse. Some STAT proteins constitutively shuttle between the nucleus and cytoplasm, whereas others require tyrosine phosphorylation for nuclear localization. In either case, the regulation of nuclear trafficking can provide a target for therapeutic intervention.

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Figure 1: STAT tyrosine phosphorylation by receptor and non-receptor kinases.
Figure 2: Schematic of karyopherin-mediated nuclear trafficking.
Figure 3: STAT1 trafficking signals are integral to its DNA-binding domain.
Figure 4: STAT2 cellular localization is influenced by IRF9 or tyrosine phosphorylated STAT1.
Figure 5: Constitutive nuclear import of STAT3 is mediated by importin-α3.

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Acknowledgements

The authors thank current and past members of the Reich laboratory for their thoughtful contributions to the ins and outs of STATs. The work was supported by grants from the US National Institutes of Health.

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  1. Molecular Genetics and Microbiology, Stony Brook University, Stony Brook, New York, 11777, New York, USA

    Nancy C. Reich & Ling Liu

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  1. Nancy C. Reich
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Glossary

G-protein-coupled receptor

(GPCR). One of a large group of receptors that bind a diverse set of molecules, including chemokines, complement components, biologically active amines and neurotransmitters. GPCRs are seven-transmembrane-spanning receptors and are coupled to heterotrimeric, GTP-regulated signalling proteins.

Oncogenic tyrosine kinases

Enzymes that phosphorylate tyrosine residues, and uncontrolled activity of these enzymes promotes cancer.

Nuclear-localization signal

A protein motif that targets proteins for import to the nucleus.

Nuclear-export signal

A sequence motif that can direct the export of proteins from the nucleus.

RNA interference

The use of double-stranded RNAs with sequences that precisely match a given gene, to knock-down the expression of that gene by directing RNA-degrading enzymes to destroy the encoded mRNA transcript.

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Reich, N., Liu, L. Tracking STAT nuclear traffic. Nat Rev Immunol 6, 602–612 (2006). https://doi.org/10.1038/nri1885

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