FRS2-mediated Signals in Prostatic Tumorigenesis and Development

总结 多效性成纤维细胞生长因子（FGF）控制广泛的细胞过程，包括 前列腺发育、功能和体内平衡，通过激活四种高度同源的FGF受体 （FGFR）跨膜酪氨酸激酶。FGF信号轴的异常表达和激活是 通常发现与前列腺肿瘤的发展和进展有关。FRS 2a是一种衔接蛋白， 将FGFR激酶转化为下游信号传导靶点，其被FGFR 1差异磷酸化， 前列腺上皮细胞中的FGFR 2激酶。FRS 2a在发育中的前列腺中动态表达， 与前列腺分支形态发生、雄激素诱导的再生和肿瘤发生相关。的 该项目是为了检验FGFR亚型特异性激活FRS 2a介导的信号发挥作用的假设， 在调节前列腺上皮细胞前体细胞增殖和分化中的重要作用 发育和再生，以及FRS 2a介导的信号传导的异常激活有助于前列腺增生。 肿瘤发生，这是根据我们最近的发现制定的。努力将集中在利用基因 工程小鼠以及分子生物学，细胞生物学和生物化学技术，以了解 异常细胞信号传导如何促进前列腺肿瘤的发生和发展。具体目标是 表征对于介导FGFR信号重要的FRS 2a的结构域;表征FRS 2a的结构域， FRS 2在前列腺发育和组织稳态中的作用;并研究异常信号如何 FRS 2a介导的前列腺肿瘤的发生和发展。目标是 了解FGFR受体在底物水平的特异性信号传导以及FRS 2a介导的 前列腺发育、组织稳态和肿瘤发生中的信号。了解FGFR的作用 前列腺发育和肿瘤发生的信号将为设计新的策略提供新的思路， 预防和拦截前列腺癌的发生和发展。动物模型 在该项目中开发的这一技术不仅为进一步研究前列腺癌中的FGFR信号提供了有用的工具， 启动和进展，而且还用于评估营养和活性膳食成分对 预防、干预和中断前列腺肿瘤进展。

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.