【作者】 黄威；

【导师】 管坤良； 熊跃；

【作者基本信息】 复旦大学 ， 生物化学与分子生物学， 2013， 博士

【摘要】 Hippo信号通路通过协调细胞增殖和细胞凋亡在个体发育过程中发挥调控细胞数量和器官大小的作用,该信号通路的紊乱导致肿瘤的发生。TAZ(Transcriptional co-Activator with PDZ-binding motif或者WWTR1, WW-domain containing Transcriptional Regulator1)是Hippo信号通路下游的一个转录共激活子,TAZ蛋白过表达和乳腺癌发生密切相关。蛋白激酶LATS (Large Tumor Suppressor)是Hippo信号通路的核心蛋白之一,研究发现LATS磷酸化TAZ第89位丝氨酸,促进TAZ与14-3-3蛋白的结合,导致TAZ滞留在细胞质不能进入细胞核,同时LATS还能通过磷酸化TAZ蛋白C端的磷酸降解决定子(phosphodegron)促进TAZ的蛋白酶体降解。在这篇论文里,我们首次发现了TAZ蛋白N端的磷酸降解决定子也参与了TAZ蛋白水平的调控,并且这个过程受到细胞PI3K信号通路的调节。蛋白激酶GSK3能够磷酸化TAZ蛋白N端的磷酸降解决定子,促进TAZ和SCFβ-TrCP泛素连接酶的β-TrCP亚基结合,从而被泛素化修饰并降解。PI3K通过激活AKT对GSK3的磷酸化作用,抑制GSK3的激酶活性,从而稳定TAZ的蛋白水平。我们还观察到在PI3K通路活性较高的肿瘤细胞系中TAZ的蛋白水平也是上调的,比如抑癌基因PTEN突变缺失的癌症细胞系。这项研究首次阐明TAZ蛋白降解调控的新机制,揭示了PI3K信号通路通过TAZ来促进细胞生长以及肿瘤发生的功能。更多还原

【Abstract】 The Hippo tumor suppressor pathway plays a major role in development, organ size control by coordination cell proliferation and apoptosis, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif, TAZ or WWTR1) is a transcription co-activator acting downstream of the Hippo pathway and increased TAZ protein levels have been associated with human cancers, such as breast cancer. Previous studies have shown that TAZ is inhibited by LATS dependent phosphorylation, leading to cytoplasmic retention and ubiquitin dependent degradation. The LATS kinase, a core component of the Hippo pathway, phosphorylates the C-terminal phosphodegron in TAZ to promote its degradation. In this study we have found that the N-terminal phosphodegron of TAZ also plays a role in TAZ protein level regulation, particularly in response to different status of cellular PI3K signaling. GSK3, which can be inhibited by high PI3K via AKT dependent inhibitory phosphorylation, phosphorylates the N-terminal phosphodegron in TAZ and the phosphorylated TAZ binds to β-TrCP subunit of the SCFβ-TrCP E3ubiquitin ligase and therefore leading to TAZ ubiquitylation and degradation. We observed that TAZ protein level is elevated in tumor cells with high PI3K signaling, such as in PTEN mutant cancer cells. This study provides a novel mechanism of TAZ regulation and suggests a role of TAZ in modulating tissue growth and tumor development in response to PI3K signaling.更多还原