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J. Biol. Chem., Vol. 282, Issue 36, 26245-26256, September 7, 2007

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A Nuclear Export Sequence Located on a -Strand in Fibroblast Growth Factor-1^*

Trine Nilsen¹, Ken R. Rosendal², Vigdis Sørensen, Jørgen Wesche³, Sjur Olsnes, and Antoni Widocha⁴

From the Centre for Cancer Biomedicine, Institute for Cancer Research, Rikshospitalet-Radiumhospitalet Medical Centre, Montebello, University of Oslo, 0310 Oslo, Norway

Receptor-bound and endocytosed fibroblast growth factor-1 (FGF-1) is able to cross the vesicle membrane and translocate to cytosol and nucleus. This suggests an intracellular role of FGF-1, which also signals by activating transmembrane FGF receptors. Phosphorylation of internalized FGF-1 by nuclear protein kinase C induces rapid export from the nuclei by a leptomycin B-sensitive pathway. In the present work, we have searched for and identified a Leu-rich nuclear export sequence (NES) at the C terminus of FGF-1 required for its nuclear export and able to confer nuclear export activity to a reporter protein in an in vivo system. Mutants where hydrophobic amino acids within the NES were exchanged for alanine exhibited reduced or abolished nuclear export. As demonstrated in co-immunoprecipitation experiments, a complex containing FGF-1, exportin-1, and its co-factor Ran-GTP, was formed in vitro. Formation of this complex in vivo was demonstrated by a peroxisomal targeting assay. Formation of the FGF-1-exportin-1-Ran-GTP complex in vitro as well as nuclear export of FGF-1 in vivo was dependent on phosphorylation of FGF-1, and it was abolished by leptomycin B. The FGF-1 NES was found to be situated along a -strand, which has not been reported before, since NESs usually are -helical.

Received for publication, December 7, 2006 , and in revised form, June 29, 2007.

^* This work was supported by Blix Fund for the Promotion of Medical Research, Rachel and Otto Kr. Bruun's Fund, and the Jahre Foundation. 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 material to Figs. 4 and 6.

¹ A predoctoral fellow of the Norwegian Cancer Society.

² A postdoctoral fellow of the Norwegian Cancer Society.

³ Supported by a FUGE fellowship from the Norwegian Research Council.

⁴ To whom correspondence should be addressed. Tel.: 47-22-93-4281; Fax: 47-22-50-86-92; E-mail: antoni.wiedlocha{at}rr-research.no.

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