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Review
. 2019 Jul 13;8(7):715.
doi: 10.3390/cells8070715.

Fibroblast Growth Factor Receptor Functions in Glioblastoma

Ana Jimenez-Pascual  1 , Florian A Siebzehnrubl  2
Affiliations
Review

Fibroblast Growth Factor Receptor Functions in Glioblastoma

Ana Jimenez-Pascual et al. Cells. .

Abstract

Glioblastoma is the most lethal brain cancer in adults, with no known cure. This cancer is characterized by a pronounced genetic heterogeneity, but aberrant activation of receptor tyrosine kinase signaling is among the most frequent molecular alterations in glioblastoma. Somatic mutations of fibroblast growth factor receptors (FGFRs) are rare in these cancers, but many studies have documented that signaling through FGFRs impacts glioblastoma progression and patient survival. Small-molecule inhibitors of FGFR tyrosine kinases are currently being trialed, underlining the therapeutic potential of blocking this signaling pathway. Nevertheless, a comprehensive overview of the state of the art of the literature on FGFRs in glioblastoma is lacking. Here, we review the evidence for the biological functions of FGFRs in glioblastoma, as well as pharmacological approaches to targeting these receptors.

Keywords: FGFR; astrocytoma; brain cancer; fibroblast growth factor; malignant glioma; review.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
Domain structure of FGFRs: an extracellular domain containing ligand binding site is followed by a single transmembrane domain, and an intracellular domain containing split tyrosine kinases. Left panel: organization of the FGF–FGFR complex at the cell surface. The FGF–FGFR complex is stabilized by a heparin/HS chain of the HS proteoglycan (HSPG). Right panel: The extracellular domain of the receptor is composed of three Ig-like domains: Ig-I, Ig-II, and Ig-III. Ig-I has autoinhibitory capacity while Ig-II and Ig-III form the ligand binding domain. Ig-II contains the heparin/HS binding site (HBS) and is separated from Ig-I by an acid box (AB). The cytoplasmic domain is formed by two tyrosine kinases: tyrosine kinase 1 (TK1) and tyrosine kinase 2 (TK2). Image created with biorender.com.
Figure 2
Figure 2
Schematic representation of FGFR splice isoforms. The Ig-III domain of FGFR1–3 is encoded by exons 7–9. Exon 7 encodes Ig-IIIa, which consists of the N-terminal half of the Ig-III loop. The C-terminal half is formed by the IIIb or IIIc sequence, which is generated by the selective inclusion of exons 8 or 9, respectively. Truncation of the Ig-I loop creates FGFRβ isoforms (dotted line), while the full-length receptor is termed FGFRα. Image created with biorender.com.
Figure 3
Figure 3
FGFR signaling pathway. After ligand binding, FGFRs dimerize and activate multiple signal transduction pathways. Each pathway induces the expression of specific target genes related to cell proliferation (STATs, RAS/p38/JNKs, and RAS/MAPK/ERK), survival (STATs and PI3K/AKT), and cytoskeleton regulation (PLC/Ca2+). Kinases are color-coded according to their specific signaling pathway. Image created with biorender.com.
Figure 4
Figure 4
FGFR signaling pathway regulation. FGFR signaling is negatively regulated, partly by CBL (inducing FGFR degradation after receptor internalization), by SEF, SPRY, MKP1, and MPK3 (which negatively regulate proliferation and survival related pathways). FGFRs can also regulate their own activation due to the autoinhibitory function of Ig-I. Image created with biorender.com.
See this image and copyright information in PMC

References

    1. Trowell O.A., Willmer E.N. Studies on the growth of tissues in vitro VI. The effects of some tissue extracts on the growth of periosteal fibroblasts. J. Exp. Biol. 1939;16:60–70.
    1. Lee P.L., Johnson D.E., Cousens L.S., Fried V.A., Williams L.T. Purification and complementary DNA cloning of a receptor for basic fibroblast growth factor. Science. 1989;245:57–60. doi: 10.1126/science.2544996. - DOI - PubMed
    1. Beenken A., Mohammadi M. The FGF family: Biology, pathophysiology and therapy. Nat. Rev. Drug. Discov. 2009;8:235–253. doi: 10.1038/nrd2792. - DOI - PMC - PubMed
    1. Guillemot F., Zimmer C. From cradle to grave: The multiple roles of fibroblast growth factors in neural development. Neuron. 2011;71:574–588. doi: 10.1016/j.neuron.2011.08.002. - DOI - PubMed
    1. Miyake A., Hattori Y., Ohta M., Itoh N. Rat oligodendrocytes and astrocytes preferentially express fibroblast growth factor receptor-2 and -3 mRNAs. J. Neurosci. Res. 1996;45:534–541. doi: 10.1002/(SICI)1097-4547(19960901)45:5<534::AID-JNR3>3.0.CO;2-D. - DOI - PubMed

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