NGF-induced cell differentiation and gene activation is mediated by integrative nuclear FGFR1 signaling (INFS)

• Published in: PloS one Vol. 8; no. 7; p. e68931
• Main Authors: Lee, Yu-Wei, Stachowiak, Ewa K, Birkaya, Barbara, Terranova, Christopher, Capacchietti, Mariolina, Claus, Peter, Aletta, John M, Stachowiak, Michal K
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 10.07.2013; Public Library of Science (PLoS)
• Subjects: Active Transport, Cell Nucleus - drug effects; Active Transport, Cell Nucleus - genetics; Animals; Axonogenesis; Biology; Cell activation; Cell differentiation; Cell Differentiation - drug effects; Cell Nucleus - drug effects; Cell Nucleus - metabolism; Cells, Cultured; Cytoplasm; Deoxyribonucleic acid; Differentiation (biology); DNA; Doublecortin protein; Fibroblast growth factor 2; Fibroblast growth factor receptor 1; Fibroblast growth factors; Fibroblasts; Gene expression; Genes; Genetic transcription; Growth factors; Humans; Hydroxylase; Kinases; Ligands; Morphology; Nanoparticles; Nerve growth factor; Nerve Growth Factor - pharmacology; Nerve Growth Factor - physiology; Nervous system; Neurites - drug effects; Neurites - physiology; Neurosciences; Neurotrophic factors; Nuclear receptors; Nuclear transport; Nur77 protein; Nurr1 protein; Pathology; PC12 Cells; Pluripotency; Protein Transport; Proteins; Rats; Receptor, Fibroblast Growth Factor, Type 1 - physiology; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Signaling; Stem cells; Studies; Transcription; Transcription factors; Transcriptional Activation - drug effects; Tubulin; Tyrosine; Tyrosine 3-monooxygenase; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0068931

Nerve growth factor (NGF) is the founding member of the polypeptide neurotrophin family responsible for neuronal differentiation. To determine whether the effects of NGF rely upon novel Integrative Nuclear FGF Receptor-1 (FGFR1) Signaling (INFS) we utilized the PC12 clonal cell line, a long-standing benchmark model of sympathetic neuronal differentiation. We demonstrate that NGF increases expression of the fgfr1 gene and promotes trafficking of FGFR1 protein from cytoplasm to nucleus by inhibiting FGFR1 nuclear export. Nuclear-targeted dominant negative FGFR1 antagonizes NGF-induced neurite outgrowth, doublecortin (dcx) expression and activation of the tyrosine hydroxylase (th) gene promoter, while active constitutive nuclear FGFR1 mimics the effects of NGF. NGF increases the expression of dcx, th, βIII tubulin, nurr1 and nur77, fgfr1and fibroblast growth factor-2 (fgf-2) genes, while enhancing binding of FGFR1and Nur77/Nurr1 to those genes. NGF activates transcription from isolated NurRE and NBRE motifs. Nuclear FGFR1 transduces NGF activation of the Nur dimer and raises basal activity of the Nur monomer. Cooperation of nuclear FGFR1 with Nur77/Nurr1 in NGF signaling expands the integrative functions of INFS to include NGF, the first discovered pluripotent neurotrophic factor.