Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
Ontario Cancer Institute, University Health Network, Toronto, ON M5G 2M9, Canada.
Cell Metab. 2013 Jun 4;17(6):929-940. doi: 10.1016/j.cmet.2013.05.002.
The fibroblast growth factor receptor 4 (FGFR4)-R388 single-nucleotide polymorphism has been associated with cancer risk and prognosis. Here we show that the FGFR4-R388 allele yields a receptor variant that preferentially promotes STAT3/5 signaling. This STAT activation transcriptionally induces Grb14 in pancreatic endocrine cells to promote insulin secretion. Knockin mice with the FGFR4 variant allele develop pancreatic islets that secrete more insulin, a feature that is reversed through Grb14 deletion and enhanced with FGF19 administration. We also show in humans that the FGFR4-R388 allele enhances islet function and may protect against type 2 diabetes. These data support a common genetic link underlying cancer and hyperinsulinemia.
成纤维细胞生长因子受体 4 (FGFR4)-R388 单核苷酸多态性与癌症风险和预后相关。在这里，我们表明 FGFR4-R388 等位基因产生一种受体变体，该变体优先促进 STAT3/5 信号转导。这种 STAT 激活转录诱导胰腺内分泌细胞中的 Grb14 以促进胰岛素分泌。携带 FGFR4 变体等位基因的敲入小鼠发育出分泌更多胰岛素的胰岛，该特征可通过 Grb14 缺失逆转，并通过 FGF19 给药增强。我们还在人类中表明，FGFR4-R388 等位基因增强胰岛功能并可能预防 2 型糖尿病。这些数据支持癌症和高胰岛素血症的常见遗传联系。
