Receptor-specific signaling of FGFR in the prostate

描述（由申请人提供）：成纤维细胞生长因子（FGF）通过激活FGF受体（FGFR）酪氨酸激酶来控制许多细胞过程。SNT1是连接FGFR与下游信号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，四种FGFR亚型对SNT1的磷酸化和激活方式不同，其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（定性和定量）导致SNT1与不同的下游介质或效应物相关联，因此有助于FGFR激酶同型发送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效应物或介质，促进前列腺肿瘤细胞的自主生长，促进前列腺肿瘤的发展和恶性进展。目的是了解FGFR如何在底物水平诱导受体特异性信号，为FGFR信号在前列腺癌中的研究建立动物模型，以及饮食因素和药物通过改变FGFR信号在预防和治疗前列腺肿瘤进展中的作用。具体目的是表征SNT1的功能域；研究SNT1在FGFR1诱导的前列腺肿瘤发展中的作用。在昆虫细胞和哺乳动物细胞中表达的SNT1将用于体外鉴定FGFR结合域和磷酸化位点，这些位点是FGFR有丝分裂和转录激活信号传递所必需的。为了研究SNT1在FGFR信号转导中的作用，我们将构建SNT1显性阴性突变体。将产生SNT1转基因小鼠和SNT1条件敲除小鼠，以确定SNT1在异位FGFR1激酶诱导的前列腺肿瘤发展中的作用。该项目旨在验证一种新颖的观点，即通过靶向SNT1特异性破坏异位FGFR1信号可能抑制前列腺肿瘤向恶性发展。这项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在前列腺肿瘤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.