Abstract
Extracellular fibroblast growth factor 1 (FGF1) acts through cell surface tyrosine kinase receptors, but FGF1 can also act directly in the cell nucleus, as a result of nuclear import of endogenously produced, non-secreted FGF1 or by transport of extracellular FGF1 via endosomes and cytosol into the nucleus. In the nucleus, FGF1 can be phosphorylated by protein kinase C δ (PKCδ), and this event induces nuclear export of FGF1. To identify intracellular targets of FGF1 we performed affinity pull-down assays and identified nucleolin, a nuclear multifunctional protein, as an interaction partner of FGF1. We confirmed a direct nucleolin-FGF1 interaction by surface plasmon resonance and identified residues of FGF1 involved in the binding to be located within the heparin binding site. To assess the biological role of the nucleolin-FGF1 interaction, we studied the intracellular trafficking of FGF1. In nucleolin depleted cells, exogenous FGF1 was endocytosed and translocated to the cytosol and nucleus, but FGF1 was not phosphorylated by PKCδ or exported from the nucleus. Using FGF1 mutants with reduced binding to nucleolin and a FGF1-phosphomimetic mutant, we showed that the nucleolin-FGF1 interaction is critical for the intranuclear phosphorylation of FGF1 by PKCδ and thereby the regulation of nuclear export of FGF1.
Highlights
Fibroblast growth factor 1 (FGF1) belongs to the heparin binding fibroblast growth factor family, which consists of 22 members involved in a variety of cellular responses during embryonic development and in adult organisms
These experiments show that FGF1 or FGF2 can form a complex with nucleolin
In this study we show that FGF1 interacts with the nuclear protein nucleolin, and that nucleolin regulates nucleocytoplasmic trafficking of FGF1
Summary
Fibroblast growth factor 1 (FGF1) belongs to the heparin binding fibroblast growth factor family, which consists of 22 members involved in a variety of cellular responses during embryonic development and in adult organisms. FGF1 regulates proliferation, differentiation, cell survival, and apoptosis [1]. In addition to activation of FGFRs and their downstream signaling pathways, extracellular FGF1 can cross cellular membrane and translocate to the cytosol and nucleus [3,4]. Nuclear FGF1 has been implicated in DNA synthesis and proliferation [7], and it has been shown to play a role in cell differentiation, survival and in modulating p53-induced apoptosis [5,6,8]. In addition to FGF1, exogenous FGF2, epidermal growth factors (EGFs), cytokines, as well as receptors such as EGF receptors, FGFR1, and FGFR2, can be transported to the nucleus where they regulate cellular activities such as proliferation, survival and tumor progression [3,4,9,10,11,12]
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