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Originally published online as doi:10.1189/jlb.1003496 on January 23, 2004

Published online before print January 23, 2004
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(Journal of Leukocyte Biology. 2004;75:792-797.)
© 2004 by Society for Leukocyte Biology

Preassociation of nonactivated STAT3 molecules demonstrated in living cells using bioluminescence resonance energy transfer: a new model of STAT activation?

Martina Schröder*,1, Karen M. Kroeger{dagger}, Hans-Dieter Volk*, Karin A. Eidne{dagger} and Gerald Grütz*

* Institute of Medical Immunology, Humboldt-University (Charite) Berlin, Germany; and
{dagger} The Center for Medical Research, University of Western Australia, The Western Australian Institute for Medical Research, Sir Charles Gairdner Hospital, Nedlands, Perth, Australia

1Correspondence at present address: Department of Biochemistry, Trinity College, College Green, Dublin 2, Ireland. E-mail: schrodem{at}tcd.ie

Signal transducers and activators of transcription (STATs) are crucial molecules in cytokine signaling. In the conventional model of STAT activation, STAT molecules are recruited from a latent pool of cytoplasmic monomers to the activated cytokine receptor. After binding to the receptor, they get tyrosine-phosphorylated, dissociate from the receptor, and translocate to the nucleus as activation-induced dimers. Recently, several publications questioned this model of STAT activation and showed the existence of preassociated STAT molecules before activation. We were able to demonstrate the existence of these preassociated STAT3 molecules in living mammalian cells using bioluminescence resonance energy transfer. Our results support the new hypothesis that STAT molecules exist in the cytoplasm as dimers or multimers and point to an activation-induced change in STAT3 conformation. Therefore, we propose a new model of STAT activation and discuss a hypothetical structure of "cytoplasmic" STAT dimers as opposed to the known "activation-induced" dimer.

Key Words: cytokine • signal transduction • dimerization signal transducer and activator of transcription (STAT) • energy transfer • BRET




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