Ets1 and FGFR FUNCTIONS IN EPITHELIAL CELL MIGRATION

我们已经确定了一种进化上保守的导致成纤维细胞生长因子受体的新突变机制 (FGFR)在细胞表面过度积聚。这种现象在果蝇突变体中观察到，在 恶性肾细胞癌(RCC)培养。可能的原因是冯·希佩尔-林道基因的突变 肿瘤抑制基因(VHL)。还注意到过度积累的FGFR导致了细胞的异常 Ets1活性的迁移和诱导。基于这些和其他初步数据，提出了一个假设 这将研究FGFR积聚表型背后的新的细胞内机制以及如何 这种异常的信号事件，通过Ets1，可以调节细胞的运动。我们怀疑这条路径至少部分地 通过影响整合素的活性来提高细胞的运动性。我们将利用体外和体内模型 系统，并使用跨物种比较研究来剖析信号机制。目标1将 剖析导致FGFR过度积聚的囊泡转运途径及调控失调的影响 信号事件。目标2将分析Ets1在调节整合素活性中的作用，与其相关 潜在的靶基因Skap55和整合素|34。目标3将检查体内的功能关系 以果蝇和Etsl基因敲除小鼠原代细胞为模型，研究Etsl和整合素之间的相互作用。最后， 这项研究中确定的重要标记基因将在人类肿瘤样本中得到验证。

We have identified an evolutionarily conserved novel mutational mechanism that leads to FGF receptor (FGFR) over-accumulates on the cell surface. This phenomenon is observed in the Drosophila mutant and in the malignant renal cell carcinoma (RCC) culture. The likely cause is the mutation in the von Hippel-Lindau tumor suppressor gene (VHL). It was also noted that the over-accumulated FGFR leads to aberrant cell migration and induction of Etsl activity. Based on these and other preliminary data, a hypothesis is proposed that will study the novel intracellular mechanism that underlies the FGFR accumulation phenotype and how this aberrant signaling event, via Etsl, can modulate cell motility. We suspect that the pathway at least in part confers elevated cell motility by affecting integrin activities. We will utilize in vitro and in vivo model systems and employ cross-species comparative studies to dissect the signaling mechanisms. Aim 1 will dissect the vesicle transport pathway that results in FGFR over-accumulation and the effects of dysregulated signaling events. Aim 2 will analyze the role of Etsl in modulating the integrin activities, in relation to its potential target genes Skap55 and integrin |34. Aim 3 will examine the in vivo functional relationship between Etsl and integrins using Drosophila and Etsl knockout mouse primary cells as models. Finally, the important marker genes identified in this study will be verified in human tumor samples.