Note to users. If you're seeing this message, it means that your browser cannot find this page's style/presentation instructions -- or possibly that you are using a browser that does not support current Web standards. Find out more about why this message is appearing, and what you can do to make your experience of our site the best it can be.
Subscribe

Logo for

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: riku.fagerlund@ktl.fi.

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

THIS ARTICLE HAS BEEN CITED BY OTHER ARTICLES:
Membrane Microdomains and Cytoskeleton Organization Shape and Regulate the IL-7 Receptor Signalosome in Human CD4 T-cells.
B. Tamarit, F. Bugault, A.-H. Pillet, V. Lavergne, P. Bochet, N. Garin, U. Schwarz, J. Theze, and T. Rose (2013)
J. Biol. Chem. 288, 8691-8701
   Abstract »    Full Text »    PDF »
Phosphorylation of Yeast Hexokinase 2 Regulates Its Nucleocytoplasmic Shuttling.
P. Fernandez-Garcia, R. Pelaez, P. Herrero, and F. Moreno (2012)
J. Biol. Chem. 287, 42151-42164
   Abstract »    Full Text »    PDF »
Nuclear localization signal in a cancer-related transcriptional regulator protein NAC1.
K. Okazaki, N. Nakayama, Y. Nariai, K. Nakayama, K. Miyazaki, R. Maruyama, H. Kato, S. Kosugi, T. Urano, and G. Sakashita (2012)
Carcinogenesis 33, 1854-1862
   Abstract »    Full Text »    PDF »
Characterization of the interaction between the influenza A virus polymerase subunit PB1 and the host nuclear import factor Ran-binding protein 5.
E. C. Hutchinson, O. E. Orr, S. Man Liu, O. G. Engelhardt, and E. Fodor (2011)
J. Gen. Virol. 92, 1859-1869
   Abstract »    Full Text »    PDF »
HDAC4-Regulated STAT1 Activation Mediates Platinum Resistance in Ovarian Cancer.
E. A. Stronach, A. Alfraidi, N. Rama, C. Datler, J. B. Studd, R. Agarwal, T. G. Guney, C. Gourley, B. T. Hennessy, G. B. Mills, et al. (2011)
Cancer Res. 71, 4412-4422
   Abstract »    Full Text »    PDF »
Nucleocytoplasmic Distribution Is Required for Activation of Resistance by the Potato NB-LRR Receptor Rx1 and Is Balanced by Its Functional Domains.
E. Slootweg, J. Roosien, L. N. Spiridon, A.-J. Petrescu, W. Tameling, M. Joosten, R. Pomp, C. van Schaik, R. Dees, J. W. Borst, et al. (2010)
PLANT CELL 22, 4195-4215
   Abstract »    Full Text »    PDF »
Ebolavirus VP24 Binding to Karyopherins Is Required for Inhibition of Interferon Signaling.
M. Mateo, St. P. Reid, L. W. Leung, C. F. Basler, and V. E. Volchkov (2010)
J. Virol. 84, 1169-1175
   Abstract »    Full Text »    PDF »
Hantaan Virus Nucleocapsid Protein Binds to Importin {alpha} Proteins and Inhibits Tumor Necrosis Factor Alpha-Induced Activation of Nuclear Factor Kappa B.
S. L. Taylor, N. Frias-Staheli, A. Garcia-Sastre, and C. S. Schmaljohn (2009)
J. Virol. 83, 1271-1279
   Abstract »    Full Text »    PDF »
Recruitment of Stat1 to chromatin is required for interferon-induced serine phosphorylation of Stat1 transactivation domain.
I. Sadzak, M. Schiff, I. Gattermeier, R. Glinitzer, I. Sauer, A. Saalmuller, E. Yang, B. Schaljo, and P. Kovarik (2008)
PNAS 105, 8944-8949
   Abstract »    Full Text »    PDF »
Drosophila Importin {alpha}1 Performs Paralog-Specific Functions Essential For Gametogenesis.
R. Ratan, D. A. Mason, B. Sinnot, D. S. Goldfarb, and R. J. Fleming (2008)
Genetics 178, 839-850
   Abstract »    Full Text »    PDF »
A TAT DEF Elk-1 Peptide Regulates the Cytonuclear Trafficking of Elk-1 and Controls Cytoskeleton Dynamics.
J. Lavaur, F. Bernard, P. Trifilieff, V. Pascoli, V. Kappes, C. Pages, P. Vanhoutte, and J. Caboche (2007)
J. Neurosci. 27, 14448-14458
   Abstract »    Full Text »    PDF »
Nuclear and Nucleolar Targeting of Influenza A Virus NS1 Protein: Striking Differences between Different Virus Subtypes.
K. Melen, L. Kinnunen, R. Fagerlund, N. Ikonen, K. Y. Twu, R. M. Krug, and I. Julkunen (2007)
J. Virol. 81, 5995-6006
   Abstract »    Full Text »    PDF »
Mapuera virus, a rubulavirus that inhibits interferon signalling in a wide variety of mammalian cells without degrading STATs.
K. Hagmaier, N. Stock, B. Precious, K. Childs, L.-F. Wang, S. Goodbourn, and R. E. Randall (2007)
J. Gen. Virol. 88, 956-966
   Abstract »    Full Text »    PDF »
Classical Nuclear Localization Signals: Definition, Function, and Interaction with Importin {alpha}.
A. Lange, R. E. Mills, C. J. Lange, M. Stewart, S. E. Devine, and A. H. Corbett (2007)
J. Biol. Chem. 282, 5101-5105
   Abstract »    Full Text »    PDF »
Ebola Virus VP24 Binds Karyopherin {alpha}1 and Blocks STAT1 Nuclear Accumulation.
St. P. Reid, L. W. Leung, A. L. Hartman, O. Martinez, M. L. Shaw, C. Carbonnelle, V. E. Volchkov, S. T. Nichol, and C. F. Basler (2006)
J. Virol. 80, 5156-5167
   Abstract »    Full Text »    PDF »
IFN-type-I-mediated signaling is regulated by modulation of STAT2 nuclear export.
T. Frahm, H. Hauser, and M. Koster (2006)
J. Cell Sci. 119, 1092-1104
   Abstract »    Full Text »    PDF »
Nuclear Export Determines the Cytokine Sensitivity of STAT Transcription Factors.
I. Lodige, A. Marg, B. Wiesner, B. Malecova, T. Oelgeschlager, and U. Vinkemeier (2005)
J. Biol. Chem. 280, 43087-43099
   Abstract »    Full Text »    PDF »
Rabies Virus P Protein Interacts with STAT1 and Inhibits Interferon Signal Transduction Pathways.
A. Vidy, M. Chelbi-Alix, and D. Blondel (2005)
J. Virol. 79, 14411-14420
   Abstract »    Full Text »    PDF »
Simian Virus 5 V Protein Acts as an Adaptor, Linking DDB1 to STAT2, To Facilitate the Ubiquitination of STAT1.
B. Precious, K. Childs, V. Fitzpatrick-Swallow, S. Goodbourn, and R. E. Randall (2005)
J. Virol. 79, 13434-13441
   Abstract »    Full Text »    PDF »
Severe Acute Respiratory Syndrome Coronavirus Fails To Activate Cytokine-Mediated Innate Immune Responses in Cultured Human Monocyte-Derived Dendritic Cells.
T. Ziegler, S. Matikainen, E. Ronkko, P. Osterlund, M. Sillanpaa, J. Siren, R. Fagerlund, M. Immonen, K. Melen, and I. Julkunen (2005)
J. Virol. 79, 13800-13805
   Abstract »    Full Text »    PDF »
NF-{kappa}B Is Transported into the Nucleus by Importin {alpha}3 and Importin {alpha}4.
R. Fagerlund, L. Kinnunen, M. Kohler, I. Julkunen, and K. Melen (2005)
J. Biol. Chem. 280, 15942-15951
   Abstract »    Full Text »    PDF »
Nuclear and Mitochondrial Localization Signals Overlap within Bovine Herpesvirus 1 Tegument Protein VP22.
J. Zhu, Z. Qiu, C. Wiese, Y. Ishii, J. Friedrichsen, G. Rajashekara, and G. A. Splitter (2005)
J. Biol. Chem. 280, 16038-16044
   Abstract »    Full Text »    PDF »
Phosphotyrosine Signaling Networks in Epidermal Growth Factor Receptor Overexpressing Squamous Carcinoma Cells.
A. Thelemann, F. Petti, G. Griffin, K. Iwata, T. Hunt, T. Settinari, D. Fenyo, N. Gibson, and J. D. Haley (2005)
Mol. Cell. Proteomics 4, 356-376
   Abstract »    Full Text »    PDF »
Implications of an antiparallel dimeric structure of nonphosphorylated STAT1 for the activation-inactivation cycle.
M. Zhong, M. A. Henriksen, K. Takeuchi, O. Schaefer, B. Liu, J. t. Hoeve, Z. Ren, X. Mao, X. Chen, K. Shuai, et al. (2005)
PNAS 102, 3966-3971
   Abstract »    Full Text »    PDF »
Getting the message across, STAT! Design principles of a molecular signaling circuit.
U. Vinkemeier (2004)
J. Cell Biol. 167, 197-201
   Abstract »    Full Text »    PDF »
STAT2 Nuclear Trafficking.
G. Banninger and N. C. Reich (2004)
J. Biol. Chem. 279, 39199-39206
   Abstract »    Full Text »    PDF »
Nucleocytoplasmic shuttling by nucleoporins Nup153 and Nup214 and CRM1-dependent nuclear export control the subcellular distribution of latent Stat1.
A. Marg, Y. Shan, T. Meyer, T. Meissner, M. Brandenburg, and U. Vinkemeier (2004)
J. Cell Biol. 165, 823-833
   Abstract »    Full Text »    PDF »
Arginine Methylation of RNA Helicase A Determines Its Subcellular Localization.
W. A. Smith, B. T. Schurter, F. Wong-Staal, and M. David (2004)
J. Biol. Chem. 279, 22795-22798
   Abstract »    Full Text »    PDF »
Catalytic Activity Is Required for Calcium/Calmodulin-dependent Protein Kinase IV to Enter the Nucleus.
S. M. Lemrow, K. A. Anderson, J. D. Joseph, T. J. Ribar, P. K. Noeldner, and A. R. Means (2004)
J. Biol. Chem. 279, 11664-11671
   Abstract »    Full Text »    PDF »
The Coactivator of Transcription CREB-binding Protein Interacts Preferentially with the Glycosylated Form of Stat5.
C. Gewinner, G. Hart, N. Zachara, R. Cole, C. Beisenherz-Huss, and B. Groner (2004)
J. Biol. Chem. 279, 3563-3572
   Abstract »    Full Text »    PDF »
DNA binding controls inactivation and nuclear accumulation of the transcription factor Stat1.
T. Meyer, A. Marg, P. Lemke, B. Wiesner, and U. Vinkemeier (2003)
Genes & Dev. 17, 1992-2005
   Abstract »    Full Text »    PDF »
The Ins and Outs of STAT1 Nuclear Transport.
K. M. McBride and N. C. Reich (2003)
Sci. STKE 2003, re13
   Abstract »    Full Text »    PDF »
A Novel Sequence in the Coiled-coil Domain of Stat3 Essential for Its Nuclear Translocation.
J. Ma, T. Zhang, V. Novotny-Diermayr, A. L. C. Tan, and X. Cao (2003)
J. Biol. Chem. 278, 29252-29260
   Abstract »    Full Text »    PDF »
Importin {alpha} Nuclear Localization Signal Binding Sites for STAT1, STAT2, and Influenza A Virus Nucleoprotein.
K. Melen, R. Fagerlund, J. Franke, M. Kohler, L. Kinnunen, and I. Julkunen (2003)
J. Biol. Chem. 278, 28193-28200
   Abstract »    Full Text »    PDF »

To Advertise     Find Products

Science Signaling. ISSN 1937-9145 (online), 1945-0877 (print). Pre-2008: Science's STKE. ISSN 1525-8882