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Fibroblast growth factors (FGFs) comprise a family of at least 23 structurally related proteins that are involved in a multitude of physiological and pathological cellular processes including: cell growth, proliferation and differentiation, angiogenesis, chemotaxis, apoptosis, wound healing and tumorigenesis (1, 2). The biological activities of the FGFs are mediated by a family of type I transmembrane tyrosine kinases (3). Four distinct genes encoding closely related FGF receptors, FGF R1 - 4, have been identified (4). The FGF Rs have several alternatively spliced isoforms that exhibit variability in ligand affinity, expression patterns, and signaling properties (5 - 10).
Heparin or heparin sulfate proteoglycans are important cofactors mediating the interaction of FGF with FGF Rs (11 - 14). Binding of FGF to FGF R3, results in receptor dimerization, followed by trans-autophosphorylation of several tyrosine residues in the tyrosine kinase domain (7, 12, 15). Structurally, the extracellular portion of FGF R3 contains three immunoglobulin (Ig) domains; the first two are separated by a stretch of acidic amino acids termed the acid box (3). FGF R3 contains a single transmembrane domain and dual intracellular tyrosine kinase domains (3).
During human development, FGF R3 expression is enriched in brain, lung intestine, kidney, skin, growth plate, and calvarial bone (16). Point mutations in FGF R3 have been described for several skeletal disorders, including hypochondroplasia (17), thanatophoric dysplasia (18), SADDAN (severe achondroplasia with developmental delay and acanthosis nigricans) (19), craniosynostosis (20) and Crouzon syndrome with acanthosis nigricans (21). Consistent with a role in skeletal development, more than 97% of individuals with achondroplasia, the most common form of dwarfism, exhibit a Gly380Arg activating mutation in the FGF R3 transmembrane domain (22). As with many other growth factor receptors, activating mutations in FGF R3 can be oncogenic (23). For example, FGF R3 mutations have been identified in colorectal (24), and bladder (25) cancers. In addition, about 20% of multiple myeloma cases and derived cell lines exhibit a chromosomal translocation event that results in the expression of FGF R3 on the plasma cell surface (26 - 28). The complex patterns of expression of the FGF Rs as well as the specificity of their interactions with the various FGF ligand family members are active areas of investigation.
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