Extracellular point mutations in FGFR2 result in elevated ERK1/2 activation and perturbation of neuronal differentiation
Extracellular point mutations in FGFR2 result in elevated ERK1/2 activation and perturbation of neuronal differentiation
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DOI：
10.1042/bj20070859
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发表时间：
2008-02-15
影响因子：
4.1
通讯作者：
Ladbury, John E.
中科院分区：
文献类型：
--
作者：
Schueller, Annika C.;Ahmed, Zamal;Ladbury, John E.
FGFR 2（成纤维细胞生长因子受体2）胞外区的两个独立的功能获得性点突变（S252 W和P253 R）增加了对生长因子的结合亲和力。预期这些突变体增强生长因子结合的作用是增加FGFR 2的常规信号传导途径的激活，这是由于在任何给定时间有更多受体被配体接合。使用PC 12（嗜铬细胞瘤）细胞作为模型细胞系统，我们研究了这些突变对蛋白磷酸化（包括受体）、下游信号通路的激活和细胞分化的影响。我们的研究结果表明，这两种细胞外突变的影响有意想不到的细胞内表型和细胞反应。受体磷酸化在配体刺激和未刺激状态下均发生改变。突变体还导致了一些细胞内蛋白质的差异磷酸化。两种突变均导致ERK 1/2（细胞外信号调节激酶1/2）激活增强。虽然ERK 1/2激活被认为是抑制导致细胞分化的信号，但这种反应在表达突变受体的细胞中被废除。本研究的结果表明，FGFR 2中的单个细胞外点突变对细胞内信号传导并最终对细胞命运具有深远的影响。
Two independent gain-of-function point mutations (S252W and P253R) in the extracellular region of the FGFR2 (fibroblast growth factor receptor 2) increase the binding affinity for the growth factor. The effect of this enhanced growth factor binding by these mutants is expected to be an increase in activation of regular signalling pathways from FGFR2 as a result of more receptors being engaged by ligand at any given time. Using PC12 (pheochromocytoma) cells as a model cell system we investigated the effect of these mutations on protein phosphorylation including the receptor, the activation of downstream signalling pathways and cell differentiation. Our results show that the effects of both of these extracellular mutations have unexpected intracellular phenotypes and cellular responses. Receptor phosphorylation was altered in both the ligand-stimulated and unstimulated states. The mutants also resulted in differential phosphorylation of a number of intracellular proteins. Both mutations resulted in enhanced ERK1/2 (extracellular-signal regulated kinase1/2) activation. Although ERK1/2 activation is believed to transduce signals resulting in cell differentiation, this response was abrogated in the cells expressing the mutant receptors. The results of the present study demonstrate that single extracellular point mutations in the FGFR2 have a profound effect on intracellular signalling and ultimately on cell fate.