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N-domain–dependent nonphosphorylated STAT4 dimers required for cytokine-driven activation

Nature Immunologyvolume 5pages208215 (2004) | Download Citation



The N-terminal protein interaction domain (N-domain) of the signal transducer and activator of transcription-4 (STAT4) is believed to stabilize interactions between two phosphorylated STAT4 dimers to form STAT4 tetramers. Here, we show that nonphosphorylated STAT4 dimers form in vivo before cytokine receptor–driven activation. Mutations in the N-domain dimerization interface abolished assembly of nonphosphorylated STAT4 dimers and prevented STAT4 phosphorylation mediated by cytokine receptors. In addition, N-domain dimerization occurred for other STAT family members but was homotypic in character. This implies a conserved role for N-domain dimerization, which might include influencing interactions with cytokine receptors, favoring homodimer formation or accelerating formation of the phosphorylated STAT dimer.

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The authors thank G.R. Stark (Lerner Research Institute, Cleveland, Ohio, USA) for providing the U3A cells, and J.D. Farrar (University of Texas Southwestern Medical Center, Dallas, Texas, USA) for helpful discussions.

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  1. Department of Pathology & Immunology, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    • Naruhisa Ota
    • , Tom J Brett
    • , Theresa L Murphy
    • , Daved H Fremont
    •  & Kenneth M Murphy
  2. Howard Hughes Medical Institute, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    • Naruhisa Ota
    •  & Kenneth M Murphy
  3. Department of Biochemistry and Molecular Biophysics, Washington University School of Medicine, 660 S. Euclid Avenue, St. Louis, 63110, Missouri, USA

    • Daved H Fremont


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The authors declare no competing financial interests.

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Correspondence to Kenneth M Murphy.

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