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J. Biol. Chem., Vol. 283, Issue 20, 14109-14119, May 16, 2008

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RanBP10 Is a Cytoplasmic Guanine Nucleotide Exchange Factor That Modulates Noncentrosomal Microtubules^*

Harald Schulze¹, Marei Dose, Manav Korpal, Imke Meyer^¶, Joseph E. Italiano, Jr.^||, and Ramesh A. Shivdasani^||2

From the Dana-Farber Cancer Institute, the Department of Medicine, Harvard Medical School, and ^||Brigham & Women's Hospital, Boston, Massachusetts 02115 and the ^¶Department of Pediatrics, Charité-Universitätsmedizin Berlin, 10017 Berlin, Germany

Microtubule spindle assembly in mitosis is stimulated by Ran·GTP, which is generated along condensed chromosomes by the guanine nucleotide exchange factor (GEF) RCC1. This relationship suggests that similar activities might modulate other microtubule structures. Interphase microtubules usually extend from the centrosome, although noncentrosomal microtubules function in some differentiated cells, including megakaryocytes. In these cells, platelet biogenesis requires massive mobilization of microtubules in the cell periphery, where they form proplatelets, the immediate precursors of platelets, in the apparent absence of centrioles. Here we identify a cytoplasmic Ran-binding protein, RanBP10, as a factor that binds β-tubulin and associates with megakaryocyte microtubules. Unexpectedly, RanBP10 harbors GEF activity toward Ran. A point mutation in the candidate GEF domain abolishes exchange activity, and our results implicate RanBP10 as a localized cytoplasmic Ran-GEF. RNA interference-mediated loss of RanBP10 in cultured megakaryocytes disrupts microtubule organization. These results lead us to propose that spatiotemporally restricted generation of cytoplasmic Ran·GTP may influence organization of the specialized microtubules required in thrombopoiesis and that RanBP10 might serve as a molecular link between Ran and noncentrosomal microtubules.

Received for publication, November 15, 2007 , and in revised form, March 7, 2008.

^* This work was supported, in whole or in part, by National Institutes of Health Grant R01HL63143. This work was also supported by a Scholar Award from the Leukemia and Lymphoma Society (to R. A. S.). 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1 and S2.

¹ Supported in part by Deutsche Forschungsgemeinschaft Fellowships SCHU1421/2-1 and SCHU1421/3-1. To whom correspondence may be addressed: Labor für Pädiatrische Molekularbiologie, Ziegelstrasse 5-9, 10098 Berlin, Germany. Tel.: 49-30-450-566-185; Fax: 49-30-450-566-913; E-mail: harald.schulze{at}charite.de.

² To whom correspondence may be addressed: Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115. Tel.: 617-632-5746; Fax: 617-582-8490; E-mail: ramesh_shivdasani{at}dfci.harvard.edu.

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