作为原癌基因Src家族成员之一，FRK却发挥着独特的肿瘤抑制功能，但机制不明。前期研究中，我们率先发现FRK抑制胶质瘤的增殖，新近又观察到FRK与促癌因子YAP的表达在脑胶质瘤组织中成负相关；FRK可以非Hippo依赖的方式下调YAP水平，促进YAP的酪氨酸磷酸化与泛素化降解，而YAP与泛素连接酶Siah1有结合。据此，我们提出“FRK通过磷酸化YAP，促进其与泛素连接酶Siah1结合而降解，从而抑制肿瘤增殖”的科学假说。本项目拟采用培养的细胞、裸鼠肿瘤模型与脑胶质瘤标本，研究FRK促进YAP泛素化降解进而抑制肿瘤的机制，阐明一条YAP不依赖Hippo通路、因FRK缺失而激活、促进肿瘤增殖的新的信号通路；揭示Siah1是YAP的E3泛素连接酶；阐明FRK的缺失与YAP的高表达是脑胶质瘤不良预后的分子标记物，为临床高表达YAP的胶质瘤患者采取手术联合靶向YAP的个性化综合治疗提供有益的思路。

Non-receptor tyrosine kinase Fyn-related kinase (FRK), as a member of the oncogene Src family, plays a unique tumor suppressor function. However, the molecular mechanism of FRK on tumor progression is largely unknown. Previously, we firstly reported that FRK inhibits the progression of gliomas. Recently, we found that the protein level of FRK and YAP in glioma tissues exhibited negative correlation. FRK over-expression promoted the tyrosine phosphorylation, ubiquitination and degradation of YAP as a Hippo-independent manner. More excitingly, YAP and Siah1 E3 ligase formed a protein compex. Therefore, we proposed the following hypothesis that FRK inhibits glioma progression by tyrosine phosphorylating YAP and then promoting the interaction of YAP with Siah1 E3 ligase, leading to YAP ubiquitination and degradation. By using the glioma specimens, cultured glioma cells and nude mice, we aimed to explore the molecular mechanism of FRK on YAP ubiquitination/degradation and glioma progression. Our results will identify a new signal pathway that YAP is activated, as a Hippo-independent manner, due to FRK deficiency and promotes glioma progression. In addition, our results will find that Siah1 is a potential E3 ligase for YAP. Furthermore, our results will also indicate that FRK down-regulation combind with YAP activation are the good marker for glioma patient poor prognosis and provide valuable idea for designing small molecules targeting FRK and YAP and for molecular therapy of brain gliomas.