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Sixteen years and counting: The current understanding of fibroblast growth factor receptor 3 (FGFR3) signaling in skeletal dysplasias

Authors

  • Silvie Foldynova-Trantirkova,

    1. Institute of Parasitology, Biology Centre AS CR, v.v.i., Ceske Budejovice, Czech Republic
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  • William R. Wilcox,

    1. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    2. Department of Pediatrics, UCLA School of Medicine, Los Angeles, California
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  • Pavel Krejci

    Corresponding author
    1. Medical Genetics Institute, Cedars-Sinai Medical Center, Los Angeles, California
    2. Department of Pediatrics, UCLA School of Medicine, Los Angeles, California
    3. Department of Animal Physiology and Immunology, Institute of Experimental Biology, Masaryk University, Brno, Czech Republic
    4. Department of Cytokinetics, Institute of Biophysics AS CR, v.v.i., Brno, Czech Republic
    • Department of Cytokinetics, Institute of Biophysics AS CR, v.v.i., Kralovopolska 135, CZ-612 65 Brno, Czech Republic
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  • Communicated by Arupa Ganguly

Abstract

In 1994, the field of bone biology was significantly advanced by the discovery that activating mutations in the fibroblast growth factor receptor 3 (FGFR3) receptor tyrosine kinase (TK) account for the common genetic form of dwarfism in humans, achondroplasia (ACH). Other conditions soon followed, with the list of human disorders caused by FGFR3 mutations now reaching at least 10. An array of vastly different diagnoses is caused by similar mutations in FGFR3, including syndromes affecting skeletal development (hypochondroplasia [HCH], ACH, thanatophoric dysplasia [TD]), skin (epidermal nevi, seborrhaeic keratosis, acanthosis nigricans), and cancer (multiple myeloma [MM], prostate and bladder carcinoma, seminoma). Despite many years of research, several aspects of FGFR3 function in disease remain obscure or controversial. As FGFR3-related skeletal dysplasias are caused by growth attenuation of the cartilage, chondrocytes appear to be unique in their response to FGFR3 activation. However, the reasons why FGFR3 inhibits chondrocyte growth while causing excessive cellular proliferation in cancer are not clear. Likewise, the full spectrum of molecular events by which FGFR3 mediates its signaling is just beginning to emerge. This article describes the challenging journey to unravel the mechanisms of FGFR3 function in skeletal dysplasias, the extraordinary cellular manifestations of FGFR3 signaling in chondrocytes, and finally, the progress toward therapy for ACH and cancer. Hum Mutat 33:29–41, 2012. © 2011 Wiley Periodicals, Inc.

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