Grb2蛋白类泛素化修饰调节RPTPα—c-Src信号通路的研究

Grb2蛋白是细胞信号转导途径中起连接作用的一种重要接头蛋白，早期的研究证实Grb2蛋白可以通过SH2-C-SH3域与受体型蛋白质酪氨酸磷酸酶RPTPα特异结合并抑制RPTPα-c-Src信号通路。我们近期的研究发现Grb2蛋白可以在K56位发生类泛素化（SUMOylation）修饰，体外过表达实验初步证实这种修饰可以改变Grb2与其他蛋白质的结合从而调控信号的传递。本课题拟在此发现基础上， 重点以RPTPα-c-Src信号通路为研究对象，深入研究Grb2是否通过SUMO化修饰而与RPTPα解离，促进RPTPα与c-Src结合并去磷酸化激活c-Src。通过一系列细胞实验、动物模型等证实Grb2的SUMO化修饰可以开启RPTPα-c-Src信号通路，并进一步激活下游Src家族/FAK激酶等相关信号通路，促进肿瘤的发生及转移。

Growth factor receptor-binding protein-2 (Grb2), which contains a single Src homology (SH2) domain flanked by two SH3 domains, functions as an adaptor protein in signal transduction pathways. It is previously shown that both the Grb2 SH2 domain and C-terminal SH3 domain are involved in binding to receptor protein tyrosine phosphatase alpha (RPTPα). The interaction between RPTPα and Grb2 C-terminal SH3 domain may block access to the catalytic site, thus inhibiting RPTPα activity. Our priliminary data showed that Grb2 was sumoylated at K56 site in vitro, and this sumoylation might block interaction between Grb2 and other proteins. In this project, we try to elucidate the mechanism underlying that the sumoylated Grb2 is not able to bind to RPTPα anymore, in turn, the released RPTPα binds to c-Src, thus activating c-Src and its downsteam pathway. Using cell lines and animal model, we will test its downstream physiological effect in the activated RPTPα-c-Src pathway. All the findings should help us better know relationship between tumorigenesis and signal transduction.