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

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-beta-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.

Organically modified silica nanoparticles: A nonviral vector for in vivo gene delivery and expression in the brain

“…The inhibition of BrdUrd incorporation into the cells in SVZ and in rostral migratory stream by transfected FGFR1(SP-͞NLS) observed in the present study demonstrates that the nuclear receptor controls the proliferation of the NSPCs in situ. These findings are consistent with our previous in vitro studies that showed that FGFR1(SP-͞NLS) induces the neural progenitor cells' withdrawal from the cell cycle and initiates differentiation (46,57). Thus, ORMOSIL-mediated in vivo transfection of the SVZ cells provides an effective means for elucidating the biology of stem͞progenitor cells, allowing for the modification of these developing cells for therapeutic manipulations.…”

“…In cultured cells and in the developing rat brain, FGFR1 was associated with the peripheral cytoplasm but also with the cell nuclei (46,47). The cell-surface FGFR mediates the mitogenic effects of extracellular FGFs, whereas the nonmembrane nuclear FGFR1 signals withdrawal from the cell cycle and postmitotic growth (46). FGFR1(SP-͞NLS), which does not associate with cell membranes and is expressed specifically in the nucleus, has been shown to stimulate differentiation of human neural progenitor cells in vitro and to directly inf luence gene activities without affecting the cell survival (28, 36, 48 -55).…”

“…To be able to therapeutically manipulate the endogenous adult NSPCs in the brain SVZ, it is crucial to identify the extracellular and intracellular signals that regulate division and control the fate of these cells (44,45). In cultured cells and in the developing rat brain, FGFR1 was associated with the peripheral cytoplasm but also with the cell nuclei (46,47). The cell-surface FGFR mediates the mitogenic effects of extracellular FGFs, whereas the nonmembrane nuclear FGFR1 signals withdrawal from the cell cycle and postmitotic growth (46).…”

90-kDa Ribosomal S6 Kinase Is a Direct Target for the Nuclear Fibroblast Growth Factor Receptor 1 (FGFR1)

“…Nuclear accumulation of FGFR1 and FGF-2 were observed in different laboratories in developing brain, neurons, astrocytes, adrenal medullary cells, and fibroblasts (10). Nuclear accumulation of FGFR1 accompanied growth of astrocytes and glioma cells (11,14,19), neurons (19), differentiation of neuronal progenitor cells (21), and functional adaptations of adrenal medullary cells (12,13,20), which were prevented by transfection of the cytoplasmic/nuclear dominant negative FGFR1(TKϪ), or its exclusively nuclear derivative in which the signal peptide (SP) was replaced by an NLS.…”

“…Studies in this and other laboratories have shown that upon cell stimulation, FGFR1, a typically plasma membrane-associated protein, translocates to the cell nucleus along with nonsecreted, intracellular forms of FGF-2, which lack a signal peptide but contain a functional nuclear localization signal (NLS) (10). Nuclear FGFR1 is full-length, binds FGF-2, and has an active TK domain (11,12).…”