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.
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