A new signaling pathway in gene regulation: A role for nuclear fibroblast growth factor receptor 1 (FGFR1)
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As a transmembrane protein, FGF receptor-1 (FGFR1) transmits FGF signals across the plasma membrane and triggers intracellular signaling cascades that regulate gene expression and generate biological response. However, FGFR1 is also present inside the cell nucleus in the developing or injured rat brain. In the various cultured cells, nuclear accumulation of FGFR1 is induced by diverse stimuli. Nuclear FGFR1 is shown to colocalize with RNA transcription sites, phosphorylated RNA polymerase II, splicing factors, but not with DNA replication sites, suggesting its potential roles in transcriptional regulation. To study the roles of nuclear FGFR1 in gene transcription, two genes (tyrosine hydroxylase (TH) and the fibroblast growth factor 2 (FGF-2)) with distinct promoters were selected as models, since the expression of FGF-2 and TH genes is upregulated along with the nuclear accumulation of FGFRI1 during cell stimulation. I found that transfection of nuclear FGFR1 was sufficient to transactivate both gene promoters in a kinase-independent manner. EMSA demonstrated that nuclear FGFR1 induced protein complexes binding to specific promoter region. However, nuclear FGFR1 itself lacked autonomous transactivation domain. Further studies indicated that nuclear FGFR1 stimulated transcription in cooperation with transcriptional coactivator CBP. Co-immunoprecipitation and GST pull down demonstrate interaction between N-terminal regions of CBP and FGFR1. Nuclear FGFR1 was found to be a multi-factorial protein whose N-terminus binds CBP and C-terminal TK interacts with pp90 RSK1, an inhibitor of the CBP activity. Nuclear FGFR1 activates both the C- and the N-terminal CBP domains and augments the CBP-mediated transcription through a two-separated mechanism: (1) an indirect activation, through preventing the inhibitory RSK1 binding the CBP C-terminal domain; (2) a RSK1-insensitive activation of the CBP N-terminal domain. In human neural progenitor cells, differentiation agent dB-cAMP induced colocalization of FGFR1 and CBP within nuclear speckle-like domains. This differentiation was inhibited by the overexpression of RSK1.