Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
J Biol Chem. 2012 Jul 27;287(31):26245-53. doi: 10.1074/jbc.M112.382036. Epub 2012 Jun 12.
The Hippo tumor suppressor pathway plays a major role in development and organ size control, and its dysregulation contributes to tumorigenesis. TAZ (transcriptional co-activator with PDZ-binding motif; also known as 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 large tumor suppressor (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 SCF(β-TrCP) E3 ubiquitin ligase, thereby leading to TAZ ubiquitylation and degradation. We observed that the 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.
Hippo 肿瘤抑制通路在发育和器官大小控制中发挥着重要作用，其失调导致肿瘤发生。TAZ（与 PDZ 结合基序的转录共激活因子；也称为 WWTR1）是 Hippo 通路下游的转录共激活因子，TAZ 蛋白水平的增加与乳腺癌等人类癌症有关。先前的研究表明，TAZ 受 LATS（large tumor suppressor）依赖性磷酸化抑制，导致细胞质滞留和泛素依赖性降解。LATS 激酶是 Hippo 通路的核心组成部分，磷酸化 TAZ 的 C 端磷酸降解基序以促进其降解。在这项研究中，我们发现 TAZ 的 N 端磷酸降解基序也在 TAZ 蛋白水平调节中发挥作用，特别是在细胞 PI3K 信号状态不同时。GSK3 可以通过 AKT 依赖性抑制性磷酸化被高 PI3K 抑制，其磷酸化 TAZ 的 N 端磷酸降解基序，磷酸化的 TAZ 与 SCF（β-TrCP）E3 泛素连接酶的 β-TrCP 亚基结合，从而导致 TAZ 泛素化和降解。我们观察到在具有高 PI3K 信号的肿瘤细胞（如 PTEN 突变的癌细胞）中 TAZ 蛋白水平升高。这项研究提供了 TAZ 调节的新机制，并表明 TAZ 在响应 PI3K 信号调节组织生长和肿瘤发生中发挥作用。
