FRS2-mediated Signals in Prostatic Tumorigenesis and Development

摘要 多效性成纤维细胞生长因子(成纤维细胞生长因子)控制广泛的细胞过程，包括 通过激活四个高度同源的成纤维细胞生长因子受体，实现前列腺的发育、功能和动态平衡 (FGFR)跨膜酪氨酸激酶。成纤维细胞生长因子信号轴的异常表达和激活 常被发现与前列腺癌的发生和发展有关。FRS2a是一种连接接头蛋白 FGFR激活下游信号转导靶点，由FGFR1和FGFR1差异磷酸化 前列腺上皮细胞中的FGFR2激酶。FRS2a在发育中的前列腺中动态表达，这是 与前列腺分支形态发生、雄激素诱导的再生和肿瘤的发生有关。这个 项目是测试FGFR异构体特异性激活FRS2a介导的信号发挥作用的假设 前列腺上皮细胞增殖分化调控中的重要作用 FRS2a介导的信号异常激活与前列腺的发育和再生有关 肿瘤发生，这是根据我们最近的发现制定的。努力的重点将是利用基因 转基因小鼠以及分子生物学、细胞生物学和生化技术 异常细胞信号如何在前列腺癌的发生和发展中起作用。具体目标是 描述FRS2a的结构域，这些结构域对于介导FGFR信号很重要；为了表征FRS2a的结构域 FRS2在前列腺发育和组织动态平衡中的作用；并研究异常信号如何 FRS2a在前列腺癌的发生、发展中起重要作用。我们的目标是 了解FGFR如何在底物水平诱导受体特异性信号以及FRS2a介导的作用 前列腺发育、组织动态平衡和肿瘤发生的信号。理解FGFR的作用 前列腺发育和肿瘤发生中的信号将为设计新的治疗策略提供新的线索 前列腺癌发生和发展的未来预防和阻断。动物模型 该项目的开发不仅将为进一步研究前列腺癌的FGFR信号提供有用的工具 开始和进展，但也用于评估营养和有效饮食成分在 前列腺癌进展的预防、干预和阻断。

Summary The pleiotropic fibroblast growth factors (FGF) control a broad spectrum of cellular processes, including prostate development, function, and homeostasis, by activating the four highly homologous FGF receptor (FGFR) transmembrane tyrosine kinases. Aberrant expression and activation of the FGF signaling axis are often found associated with prostatic tumor development and progression. FRS2a is an adaptor protein linking the FGFR kinases to downstream signaling targets, which is differentially phosphorylated by the FGFR1 and FGFR2 kinases in prostate epithelial cells. FRS2a is dynamically expressed in developing prostates, which is associated with prostatic branching morphogenesis, androgen-induced regeneration, and tumorigenesis. The project is to test the hypothesis that FGFR isoform-specific activation of FRS2a-mediated signals play important roles in regulating proliferation and differentiation of precursor cells for prostatic epithelial cells during development and regeneration, and aberrant activation of FRS2a-mediated signaling contributes to prostatic tumorigenesis, which was formulated based on our recent findings. Efforts will be focused on using genetically engineered mouse as well as molecular biological, cell biological, and biochemical technologies to understand how aberrant cell signaling contributes to prostate tumor initiation and progression. The specific aims are to characterize the structural domain of FRS2a that are important for mediating FGFR signals; to characterize the role of FRS2 in prostatic development and tissue homeostasis; and to investigate how aberrant signals mediated by FRS2a contribute to prostatic tumorigenesis and tumor progression. The objective is to understand how FGFR elicits receptor specific signals at the substrate level and the roles of FRS2a-mediated signals in prostatic development, tissue homeostasis, and tumorigenesis. Understanding the role of FGFR signals in prostatic development and tumorigenesis will shed new light on designing new strategies for prevention and interception of prostate cancer initiation and progression in the future. Animal models developed in the project will provide a useful tool not only for further studying FGFR signals in prostate cancer initiation and progression, but also for assessing the role of nutrition and active dietary components on prevention, intervention, and interruption on prostate tumor progression.