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J. Biol. Chem., Vol. 279, Issue 38, 40153-40160, September 17, 2004

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Nuclear and Nucleolar Localization of 18-kDa Fibroblast Growth Factor-2 Is Controlled by C-terminal Signals^*

Zhi Sheng, John A. Lewis, and William J. Chirico¶

From the Molecular and Cellular Biology Program, School of Graduate Studies, Department of Anatomy and Cell Biology, State University of New York Downstate Medical Center, Brooklyn, New York 11203

Members of high (22-, 22.5-, 24-, and 34-kDa) and low (18-kDa) molecular mass forms of fibroblast growth factor-2 (FGF-2) regulate cell proliferation, differentiation, and migration. FGF-2s have been previously shown to accumulate in the nucleus and nucleolus. Although high molecular weight forms of FGF-2 contain at least one nuclear localization signal (NLS) in their N-terminal extension, the 18-kDa FGF-2 does not contain a standard NLS. To determine signals controlling the nuclear and subnuclear localization of the 18-kDa FGF-2, its full-length cDNA was fused to that of green fluorescent protein (GFP). The fusion protein was primarily localized to the nucleus of COS-7 and HeLa cells and accumulated in the nucleolus. The subcellular distribution was confirmed using wild type FGF-2 and FGF-2 tagged with a FLAG epitope. A 17-amino acid sequence containing two groups of basic amino acid residues separated by eight amino acid residues directed GFP and a GFP dimer into the nucleus. We systematically mutated the basic amino acid residues in this nonclassical NLS and determined the effect on nuclear and nucleolar accumulation of 18-kDa FGF-2. Lys¹¹⁹ and Arg¹²⁹ are the key amino acid residues in both nuclear and nucleolar localization, whereas Lys¹²⁸ regulates only nucleolar localization of 18-kDa FGF-2. Together, these results demonstrate that the 18-kDa FGF-2 harbors a C-terminal nonclassical bipartite NLS, a portion of which also regulates its nucleolar localization.

Received for publication, January 7, 2004 , and in revised form, June 10, 2004.

^* This work was supported by an award (0151261T) from the American Heart Association. 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 six additional figures.

^¶ To whom correspondence should be addressed: Dept. of Anatomy and Cell Biology, Box 5, State University of New York Downstate Medical Center, 450 Clarkson Ave., Brooklyn, NY 11203. Tel.: 718-270-1308; Fax: 718-270-3732; E-mail: william.chirico{at}downstate.edu.

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