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J. Biol. Chem. 277 (33): 30072-30078

© 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

Arginine/Lysine-rich Nuclear Localization Signals Mediate Interactions between Dimeric STATs and Importin alpha 5*

Riku FagerlundDagger §, Krister MelénDagger , Leena Kinnunen, and Ilkka JulkunenDagger

From the Dagger  Laboratory of Infectious Disease Immunology, Department of Microbiology and the  Diabetes and Genetic Epidemiology Unit, Department of Epidemiology and Health Promotion, National Public Health Institute, FIN-00300 Helsinki, Finland

Interferon stimulation results in tyrosine phosphorylation, dimerization, and nuclear import of STATs (signal transducers and activators of transcription). Proteins to be targeted into the nucleus usually contain nuclear localization signals (NLSs), which interact with importin alpha . Importin alpha  binds to importin beta , which docks the protein complex to nuclear pores, and the complex translocates into the nucleus. Here we show that baculovirus-produced and -activated STAT1 homodimers and STAT1-STAT2 heterodimers directly interacted with importin alpha 5 (NPI-1). This interaction was very stable and was dependent on lysines 410 and 413 of STAT1. Only STAT dimers that had two intact NLS elements, one in each monomer, were able to bind to importin alpha 5. STAT-importin alpha 5 complexes apparently consisted of two STAT and two importin alpha  molecules. STAT NLS-dependent colocalization of importin alpha 5 with STAT1 or STAT2 was seen in the nucleus of transfected cells. gamma -Activated sequence DNA elements efficiently inhibited STAT binding to importin alpha 5 suggesting that the DNA and importin alpha  binding sites are close to each other in STAT dimers. Our results demonstrate that specific NLSs in STATs mediate direct interactions of STAT dimers with importin alpha , which activates the nuclear import process.

* This study was supported by the Medical Research Council of the Academy of Finland and by the Sigrid Juselius and the Finnish Cancer Foundations.The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

§ To whom correspondence should be addressed: National Public Health Inst., Mannerheimintie 166, FIN-00300 Helsinki, Finland. Tel.: 358-9-47448377; Fax: 358-9-47448355; E-mail:

Copyright © 2002 by The American Society for Biochemistry and Molecular Biology, Inc.

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