title: 90-kDa ribosomal S6 kinase is a direct target for the nuclear fibroblast growth factor receptor 1 (FGFR1): role in FGFR1 signaling.
abstract: 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.
authors.affiliation: Department of Pathology and Anatomical Sciences, State University of New York, Buffalo, New York 142214, USA.
authors.forename: Yafang
authors.initials: Y
authors.lastname: Hu
authors.forename: Xiaohong
authors.initials: X
authors.lastname: Fang
authors.forename: Star M
authors.initials: SM
authors.lastname: Dunham
authors.forename: Claudia
authors.initials: C
authors.lastname: Prada
authors.forename: Ewa K
authors.initials: EK
authors.lastname: Stachowiak
authors.forename: Michal K
authors.initials: MK
authors.lastname: Stachowiak
mesh_terms: D000818:Animals; D001921:Brain / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D006801:Humans; D009474:Neurons / Q000166:cytology / Q000378:metabolism; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics / Q000378:metabolism*; D051496:Receptor, Fibroblast Growth Factor, Type 1; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000378:metabolism*; D038744:Ribosomal Protein S6 Kinases, 90-kDa / Q000235:genetics / Q000378:metabolism*; D013347:Subcellular Fractions / Q000378:metabolism; D020798:Two-Hybrid System Techniques
chemical_list: D017362:Cyclic AMP Response Element-Binding Protein; D017468:Receptors, Fibroblast Growth Factor; D000242:Cyclic AMP; C496348:FGFR1 protein, human; C496350:Fgfr1 protein, rat; D020794:Receptor Protein-Tyrosine Kinases; D051496:Receptor, Fibroblast Growth Factor, Type 1; C069329:RPS6KA1 protein, human; D038744:Ribosomal Protein S6 Kinases, 90-kDa; C512963:Rps6ka1 protein, rat