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Integrative nuclear FGFR1 signaling (INFS) as a part of a universal “feed-forward-and-gate” signaling module that controls cell growth and differentiation

Authors

  • Michal K. Stachowiak,

    Corresponding author
    1. Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, New York
    • Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, 317 Farber Hall, State University of New York at Buffalo, Buffalo, NY 14214.
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  • Xiaohong Fang,

    1. Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, New York
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  • Jason M. Myers,

    1. Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, New York
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  • Star M. Dunham,

    1. Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, New York
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  • Ronald Berezney,

    1. Department of Biological Sciences, State University of New York at Buffalo, Buffalo, New York
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  • Pamela A. Maher,

    1. The Scripps Research Institute, La Jolla, California
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  • Ewa K. Stachowiak

    Corresponding author
    1. Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, New York
    • Molecular and Structural Neurobiology and Gene Therapy Program, Department of Pathology and Anatomical Sciences, 317 Farber Hall, State University of New York at Buffalo, Buffalo, NY 14214.
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Abstract

A novel signaling mechanism is described through which extracellular signals and intracellular signaling pathways regulate proliferation, growth, differentiation, and other functions of cells in the nervous system. Upon cell stimulation, fibroblast growth factor receptor-1 (FGFR1), a typically plasma membrane-associated protein, is released from ER membranes into the cytosol and translocates to the cell nucleus by an importin-β-mediated transport pathway along with its ligand, FGF-2. The nuclear accumulation of FGFR1 is activated by changes in cell contacts and by stimulation of cells with growth factors, neurotransmitters and hormones as well as by a variety of different second messengers and thus was named integrative nuclear FGFR1 signaling (INFS). In the nucleus, FGFR1 localizes specifically within nuclear matrix-attached speckle-domains, which are known to be sites for RNA Pol II-mediated transcription and co-transcriptional pre-mRNA processing. In these domains, nuclear FGFR1 colocalizes with RNA transcription sites, splicing factors, modified histones, phosphorylated RNA Pol II, and signaling kinases. Within the nucleus, FGFR1 serves as a general transcriptional regulator, as indicated by its association with the majority of active nuclear centers of RNA synthesis and processing, by the ability of nuclear FGFR1 to activate structurally distinct genes located on different chromosomes and by its stimulation of multi-gene programs for cell growth and differentiation. We propose that FGFR1 is part of a universal “feed-forward-and-gate” signaling module in which classical signaling cascades initiated by specific membrane receptors transmit signals to sequence specific transcription factors (ssTFs), while INFS elicited by the same stimuli feeds the signal forward to the common coactivator, CREB-binding protein (CBP). Activation of CBP by INFS, along with the activation of ssTFs by classical signaling cascades brings about coordinated responses from structurally different genes located at different genomic loci. © 2003 Wiley-Liss, Inc.

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