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J. Biol. Chem., Vol. 279, Issue 28, 29325-29335, July 9, 2004

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90-kDa Ribosomal S6 Kinase Is a Direct Target for the Nuclear Fibroblast Growth Factor Receptor 1 (FGFR1)

ROLE IN FGFR1 SIGNALING^*

Yafang Hu, Xiaohong Fang, Star M. Dunham, Claudia Prada, Ewa K. Stachowiak, and Michal K. Stachowiak¶

From the Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, State University of New York, Buffalo, New York 142214

Fibroblast growth factor receptor 1 (FGFR1) is a transmembrane protein capable of transducing stimulation by secreted FGFs. In addition, newly synthesized FGFR1 enters the nucleus in response to cellular stimulation and during development. Nuclear FGFR1 can transactivate CRE (cAMP responsive element), activate CRE-binding protein (CREB)-binding protein (CBP) and gene activities causing cellular growth and differentiation. Here, a yeast two-hybrid assay was performed to identify FGFR1-binding proteins and the mechanism of nuclear FGFR1 action. Ten FGFR1-binding proteins were identified. Among the proteins detected with the intracellular FGFR1 domain was a 90-kDa ribosomal S6 kinase (RSK1), a regulator of CREB, CBP, and histone phosphorylation. FGFR1 bound to the N-terminal region of RSK1. The FGFR1-RSK1 interaction was confirmed by co-immunoprecipitation and colocalization in the nucleus and cytoplasm of mammalian cells. Predominantly nuclear FGFR1-RSK1 interaction was observed in the rat brain during neurogenesis and in cAMP-stimulated cultured neural cells. In TE671 cells, transfected FGFR1 colocalized and coimmunoprecipitated, almost exclusively, with nuclear RSK1. Nuclear RSK1 kinase activity and RSK1 activation of CREB were enhanced by transfected FGFR1. In contrast, kinase-deleted FGFR1 (TK–), which did not bind to RSK1 failed to stimulate nuclear RSK1 activity or RSK1 activation of CREB. Kinase inactive FGFR1 (K514A) bound effectively to nuclear RSK1, but it failed to stimulate RSK1. Thus, active FGFR1 kinase regulates the functions of nuclear RSK1. The interaction of nuclear FGFR1 with pluripotent RSK1 offers a new mechanism through which FGFR1 may control fundamental cellular processes.

Received for publication, October 9, 2003 , and in revised form, April 26, 2004.

^* This work was supported in part by National Science Foundation Grant IBN-9728923, National Institutes of Health Grants HL-49376 and NS43621-01, the American Parkinson Disease Association, and the John R. Oishei Foundation (to M. K. 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.

Present address: Experimental Medicine Section, Oral Infection and Immunity Branch, NIDCR, National Institutes of Health, Bethesda, MD 20892.

Supported by the Integrative Graduate Education and Research Traineeship Grant DGE0114330 from the National Science Foundation.

^¶ To whom correspondence should be addressed. Tel.: 716-829-3540; Fax: 716-829-2911; E-mail: mks4{at}buffalo.edu.

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