FGF-signalling in the differentiation of mouse ES cells towards ...

There are four membrane-bound FGFRs consisting of three Ig domains (domains I – III) on theextracellular side and of two tyrosine kinase domains on the intracellular side of the cell surface.The Ig-domains convey FGF-binding, determine FGF ligand selectivity (domain III) and interactwith HS (Bottcher and Niehrs 2005). The C-terminal half of Ig-domain III in FGFR1-3demonstrates alternative splicing of exon 7 to either exons 8 or 9, generating FGFR(III)b orFGFR(III)c isoforms, respectively (FGFRb or FGFRc hereafter; Figure 1-6C; (Johnson andWilliams 1993; Groth and Lardelli 2002; Eswarakumar et al. 2005)). The expression of specificFGFR-isoforms is tissue-specific, meaning ligand-receptor interactions can be regulated acrosstissues, giving a high range of interaction-potential to modulate downstream signalling pathwaysand gene expression. The intracellular kinase domains are responsible for tyrosine kinase activityleading to auto-phosphorylation and recruitment of downstream signalling components elicitingthe cellular response to ligand binding. FGFR4, which has no splice variants, resembles FGFRcisoformsboth structurally and in FGF binding-affinities (Vainikka et al. 1992).A secreted third isoform, FGFR1-3(III)a lacks the trans-membrane and intracellular kinasedomains, and although they are present in blood, their function is somewhat unclear (Johnson etal. 1990; Johnson et al. 1991; Johnson and Williams 1993; Hanneken 2001).Figure 1-6: The evolution of the FGF family, binding of FGF to FGFR and alternative splicing of the FGFR. A)The evolutionary relationships within the fibroblast growth factor (FGF) gene family. The twenty-two FGF encodinggenes are arranged into seven subfamilies. Branch lengths are proportional to the evolutionary distance between eachgene. FGF19 is the human ortholog of mouse FGF15. The FGF11 subfamily is also referred to as the intracellularFGFs (iFGFs), and the FGF15 (FGF19) family as the hormone-like FGFs (hFGFs). B) Ribbon diagram of the ternaryFGF2/heparin/FGFR1 complex showing FGF2 in yellow, D2 and D3 domains of the ligand-binding portion ofFGFR1 in green and blue, respectively, and heparin in red. C) The two isoforms of FGFR1-3 are generated by17