Fibroblast Growth Factor (FGF) and FGF Receptor Families in Bone

Fibroblast growth factors isolated from many sources act to modify the growth of cell types of epithelial, neuroectodermal, and mesenchymal origin. Structurally, the FGF family encompasses the polypeptides encoded by 23 distinct genes. FGFs function in concert with a similarly complex family of cognate signal-transducing receptors (FGFRs) and nontransducing heparan sulfate-containing proteoglycans (HSPGs), the cysteine-rich receptor (CFR), and binding proteins (BPs). FGFs and their receptors exhibit remarkably varied mechanisms regulating their expression and/or bioavailability. These mechanisms occur at multiple levels of gene expression, including transcription, translation, intracellular protein trafficking, extracellular matrix localization, and release. The FGF family can be divided into those with multiple or single promoters and/or transcription start sites. The FGF-2 promoter shows both negative and positive cis-acting regulatory domains with functional mapping. In contrast to FGF-1, the human FGF-2 gene contains one core promoter region that directs the transcription of multiple mRNAs possessing the same transcription start site. The FGF-3 gene is transcribed into multiple classes of mRNA with different transcription start sites, in mouse embryonal carcinoma cells, a human colon carcinoma cell line, mouse mammary tumors, and in developing mouse embryos. On the cell surface, at least three types of proteins may interact with the FGFs. The first class are high-affinity integral plasma membrane proteins with three extracellular immunoglobulin (Ig)-like loop structures. The second type of receptor are low-affinity binding sites, identified as HSPGs. HSPGs do not possess intrinsic tyrosine kinase activity, but are important molecules regulating FGF bioavailability. The third type of protein, a cysteine-rich FGFR (CFR), was originally isolated and characterized from chicken embryos. All three types of receptor proteins form dynamic interactions with the FGFs that are compensatory with their respective bioactivities.