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J. Biol. Chem., Vol. 280, Issue 2, 1123-1131, January 14, 2005

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STAT5B-mediated Growth Hormone Signaling Is Organized by Highly Dynamic Microtubules in Hepatic Cells^*

Thu Phung-Koskas, Antoine Pilon, Christian Poüs, Cécile Betzina, Marie Sturm, Marie-Lise Bourguet-Kondracki, Geneviève Durand, and Anne Drechou¶

From the Laboratoire de Biochimie et de Biologie Cellulaire, EA 1595, Faculté de Pharmacie, 5, rue JB. Clément, 92296 Chtenay-Malabry Cedex, France and the Laboratoire de Chimie, CNRS UMR 5154, Muséum National Histoire Naturelle, 63 rue Buffon, 75005 Paris, France

In the last decade, the notion that microtubules are critical to the spatial organization of signal transduction and contribute to the transmission of signals to downstream targets has been proposed. Because the STAT5B transduction and transcription factor is the major STAT protein activated by growth hormone stimulation in hepatocytes and is a crossroads between many signaling pathways, we studied the involvement of microtubules in STAT5B-mediated growth hormone signaling pathway in the highly differentiated and polarized WIF-B hepatic cell line. We showed that depolymerization of the microtubule network impaired STAT5B translocation to the nucleus upon growth hormone treatment. A significant amount of STAT5B binds to microtubules, while STAT5A and STAT3 are exclusively compartmentalized in the cytosol. Moreover, taxol-induced stabilization of microtubules released STAT5B from its binding, and we show that STAT5B binds specifically to the highly dynamic microtubules and is absent of the stable microtubule subpopulation. The specific involvement of dynamic microtubule subpopulation in growth hormone signaling pathway was confirmed by the inhibition of growth hormone-induced STAT5B nuclear translocation after stabilization of microtubules or specific disruption of highly dynamic microtubules. Upon growth hormone treatment, MT-bound STAT5B was rapidly released from microtubules by a dynein-dependent transport to the nucleus. Altogether, our findings indicate that the labile microtubule subpopulation specifically and dynamically organizes STAT5B-mediated growth hormone signaling in hepatic cells.

Received for publication, August 30, 2004 , and in revised form, October 12, 2004.

^* This work was supported by a grant from the Institut de Recherches Internationales Servier. The costs of publication of this article were defrayed in part by the payment of page charges. This 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. Tel.: 33-1-46-83-54-78; Fax: 33-1-46-83-58-02; E-mail: anne.drechou{at}cep.u-psud.fr.

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