FGFR2b mutants bind an expanded range of ligands

Apert sydrome is the most severe of the craniosynostosis syndromes and results almost entirely from two missense mutations in the conserved Ser252 and Pro253 residues in the IgII-IgIII linker of FGFR2 (Wilkie, 1995). These mutations affect both the 'b' and 'c' isoforms, although mutation in the FGFR2c isoform is believed to be more clinically relevant to the development of Apert syndrome (Lomri, 1998). More recently, the same mutations arising somatically have been identified in endometrial and ovarian cancer (Dutt, 2008; Byron, 2008; Pollock, 2007).<br><br><br>The IgII and IgIII domains and the intervening linker of the FGF receptor constitute a binding site for FGFs (Chellaiah, 1999; Stauber, 2000; Plotnikov, 1999). The epithelial isoform FGFR2b binds only to mesenchymally expressed ligands including FGF7 and FGF10 and does not respond to epithelial ligands FGF2, 4, 6, 8 and 9 (Ornitz, 1996). Introduction of the P252W and P252R mutations into FGFR2b allows the aberrant binding and activation by the epithelially expressed ligands FGF 2, 6 and 9, establishing an autocrine signaling loop in epithelial cells. These mutations also increase the binding affinity for the receptor's normal mesenchymal ligands 2- to 8-fold (Yu, 2000; Ibrahimi, 2004b). Based on biochemical and crystal studies, the mutations in the IgII-IgIII linker region are predicted to alter the hydrogen bonding network in this region and may change the conformation and thus the ligand-binding properties of the mutant receptors (Stauber, 2000).<br>

颅缝早闭综合征系颅缝融合综合征中最严重的一种，几乎完全由FGFR2（纤维生长因子受体2）的IgII-IgIII连接区中保守的Ser252和Pro253位点的错义突变所致（Wilkie, 1995）。这些突变影响‘b’和‘c’两种同源异构体，尽管FGFR2c同源异构体的突变被认为与颅缝早闭综合征的临床相关性更高（Lomri, 1998）。近年来，在子宫内膜癌和卵巢癌中亦发现了源自体细胞的同一突变（Dutt, 2008; Byron, 2008; Pollock, 2007）。

FGF受体（FGF纤维生长因子受体）的IgII和IgIII结构域及其间的连接区构成FGFs（FGF纤维生长因子）的结合位点（Chellaiah, 1999; Stauber, 2000; Plotnikov, 1999）。上皮型同源异构体FGFR2b仅与间充质表达的配体相结合，包括FGF7和FGF10，并对上皮配体FGF2、4、6、8和9无响应（Ornitz, 1996）。将P252W和P252R突变引入FGFR2b，使其能够异常结合并激活上皮表达的配体FGF 2、6和9，从而在上皮细胞中建立自分泌信号回路。这些突变还增加了受体对正常间充质配体2至8倍的结合亲和力（Yu, 2000; Ibrahimi, 2004b）。基于生化及晶体学研究，预测IgII-IgIII连接区中的突变将改变该区域的氢键网络，并可能改变构象，进而改变突变受体的配体结合特性（Stauber, 2000）。