Chaffee Blake R, Hoang Thanh V, Leonard Melissa R, Bruney Devin G, Wagner Brad D, Dowd Joseph Richard, Leone Gustavo, Ostrowski Michael C, Robinson Michael L
Department of Biology, Cell Molecular and Structural Biology Graduate Program, Miami University, Oxford, OH, USA.
Department of Molecular Virology, Immunology and Medical Genetics, Department of Molecular Genetics, The Comprehensive Cancer Center, The Ohio State University, Columbus, OH, USA.
Dev Biol. 2016 Feb 15;410(2):150-163. doi: 10.1016/j.ydbio.2015.12.027. Epub 2016 Jan 5.
Lens epithelial cells express many receptor tyrosine kinases (RTKs) that stimulate PI3K-AKT and RAS-RAF-MEK-ERK intracellular signaling pathways. These pathways ultimately activate the phosphorylation of key cellular transcription factors and other proteins that control proliferation, survival, metabolism, and differentiation in virtually all cells. Among RTKs in the lens, only stimulation of fibroblast growth factor receptors (FGFRs) elicits a lens epithelial cell to fiber cell differentiation response in mammals. Moreover, although the lens expresses three different Fgfr genes, the isolated removal of Fgfr2 at the lens placode stage inhibits both lens cell survival and fiber cell differentiation. Phosphatase and tensin homolog (PTEN), commonly known as a tumor suppressor, inhibits ERK and AKT activation and initiates both apoptotic pathways, and cell cycle arrest. Here, we show that the combined deletion of Fgfr2 and Pten rescues the cell death phenotype associated with Fgfr2 loss alone. Additionally, Pten removal increased AKT and ERK activation, above the levels of controls, in the presence or absence of Fgfr2. However, isolated deletion of Pten failed to stimulate ectopic fiber cell differentiation, and the combined deletion of Pten and Fgfr2 failed to restore differentiation-specific Aquaporin0 and DnaseIIβ expression in the lens fiber cells.
晶状体上皮细胞表达多种受体酪氨酸激酶（RTK），这些激酶可刺激PI3K-AKT和RAS-RAF-MEK-ERK细胞内信号通路。这些通路最终激活关键细胞转录因子和其他蛋白质的磷酸化，这些蛋白质控制着几乎所有细胞的增殖、存活、代谢和分化。在晶状体中的RTK中，在哺乳动物中只有成纤维细胞生长因子受体（FGFR）的刺激能引发晶状体上皮细胞向纤维细胞的分化反应。此外，尽管晶状体表达三种不同的Fgfr基因，但在晶状体基板阶段单独去除Fgfr2会抑制晶状体细胞存活和纤维细胞分化。磷酸酶和张力蛋白同源物（PTEN），通常被称为肿瘤抑制因子，可抑制ERK和AKT激活，并启动凋亡途径和细胞周期停滞。在这里，我们表明Fgfr2和Pten的联合缺失挽救了单独Fgfr2缺失相关的细胞死亡表型。此外，无论是否存在Fgfr2，去除Pten都会使AKT和ERK激活增加，高于对照水平。然而，单独缺失Pten未能刺激异位纤维细胞分化，Pten和Fgfr2的联合缺失也未能恢复晶状体纤维细胞中分化特异性水通道蛋白0和DnaseIIβ的表达。
