Receptor-specific signaling of FGFR in the prostate

说明书(申请人提供)：成纤维细胞生长因子通过激活成纤维细胞生长因子受体(FGFR)酪氨酸激酶来控制许多细胞过程。SNT1是连接FGFR和下游信号转导靶点的重要接头蛋白。SNT1基因的破坏会导致早期胚胎死亡。在前列腺上皮细胞中，SNT1被四种FGFR亚型不同地磷酸化和激活，并且磷酸化模式与细胞的有丝分裂活性和其他表型参数密切相关。在这里，我们假设SNT1的不同磷酸化，无论是定性的还是定量的，都导致SNT1与不同的下游介质或效应物相关联，从而有助于FGFR激酶亚型发出的信号的特异性和强度。异位FGFR1激酶异常激活SNT1，将有丝分裂信号传递给下游的效应或介体，促进前列腺肿瘤细胞的自主生长，促进前列腺癌的发生和发展。其目的是了解FGFR如何在底物水平诱导受体特异性信号，建立前列腺癌FGFR信号研究的动物模型，并通过改变FGFR信号来研究饮食因素和药物在预防和治疗前列腺癌进展中的作用。其具体目的是确定SNT1的功能结构域，研究SNT1在FGFR1诱导的前列腺癌发生中的作用。在昆虫细胞和哺乳动物细胞中表达的SNT1将用于FGFR结合域和磷酸化位点的体外鉴定，这些位点是传递FGFR有丝分裂和转录激活信号所必需的。为研究SNT1在FGFR信号转导中的作用，将构建显性负SNT1突变体。将建立SNT1转基因小鼠和SNT1状态基因敲除小鼠，以确定SNT1在异位FGFR1激酶诱导的前列腺癌发生中的作用。该项目是为了测试一种新的想法，即通过靶向SNT1特异性干扰异位FGFR1信号可能会抑制前列腺癌向恶性肿瘤的进展。本研究的结果将为设计新的策略提供信息，这些策略可能通过调节FGFR1和SNT1的活性来特异性地改变FGFR1在前列腺癌和其他相关疾病中的信号转导。

DESCRIPTION (provided by applicant): The fibroblast growth factor (FGF) controls many cellular processes through activation of the FGF receptor (FGFR) tyrosine kinase. SNT1 is an important adaptor protein linking FGFR to downstream signaling targets. Disruption of the SNT1 gene causes early embryonic lethality. SNT1 is phosphorylated and activated differently by the four FGFR isoforms in prostate epithelial cells, and the phosphorylation patterns are closely correlated to the mitogenic activity and other phenotypic parameters of cells. Here we hypothesize that differential phosphorylation of SNT1, both qualitatively and quantitatively, leads SNT1 to associate with different downstream mediators or effectors, and therefore contribute to specificity and intensity of the signals sent by FGFR kinase isotypes. Abnormal activation of SNT1 by ectopic FGFR1 kinase relays the mitogenic signals to downstream effectors or mediators and contributes to prostate tumor cell autonomous growth, and to prostate tumor development and progression to malignancy. The objective is to understand how FGFR elicits receptor specific signals at the substrate level, to develop an animal model for studies on FGFR signals in prostate cancer, and on the role of dietary factors and pharmaceutics in prevention and treatment of prostate tumor progression by alteration of FGFR signaling. The specific aims are to characterize the functional domains of SNT1; to study the roles of SNT1 in FGFR1 induced prostate tumor development. SNT1 expressed in insect cells and mammalian cells will be used for in vitro characterization of the FGFR binding domain and phosphorylation sites required for relaying FGFR mitogenic and transcription activation signals. Dominant negative SNT1 mutants will be constructed for studying the roles of SNT1 in FGFR signal transduction. SNT1 transgenic mice and SNT1 condition knockout mice will be generated to define the roles of SNT1 in prostate tumor development induced by ectopic FGFR1 kinase. The project is to test a novel idea that specifically disruption of ectopic FGFR1 signaling through targeting SNT1 may inhibit prostate tumor progression to malignancy. The results of this study will provide information for design of new strategies that may specifically alter signal transduction of FGFR1 for prostate tumor and other related diseases through regulation of activity of FGFR1 and SNT1.