FGFR-3 (IIIa), soluble

The Fibroblast growth factor receptors (FGFRs) are a family of receptor tyrosine kinases that play key roles in proliferation, differentiation, and tumorigenesis. The FGFR3 (IIIb) isoform was identified as the major family member expressed in normal human urothelium. Already in 2005 a splice variant, FGFR3ΔTM, lacking exons encoding the COOH-terminal half of immunoglobulin-like domain III and the transmembrane domain was described. Previous reports had assumed that this is would be a cancer-specific splice variant but in 2005 it was shown that FGFR3ΔTM is a normal transcript in NHU cells and is translated, N-glycosylated, and secreted. Primary urothelium expressed high levels of FGFR3ΔTM transcripts. In culture, levels were reduced in actively proliferating cells but increased at confluence and as cells approached senescence. Cells overexpressing FGFR3 IIIb showed FGF1-induced proliferation, which was inhibited by the addition of FGFR3ΔTM. In bladder tumor cell lines derived from aggressive carcinomas, there were significant alterations in the relative expression of isoforms including an overall decrease in the proportion of FGFR3ΔTM and predominant expression of FGFR3 IIIc in some cases. In summary, alternative splicing of FGFR3 IIIb in NHU cells represents a normal mechanism to generate a transcript that regulates proliferation and in bladder cancer, the ratio of FGFR3 isoforms is significantly altered.