Key Laboratory of Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology School of Medicine, Lab, Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.
J Biol Chem. 2011 Feb 18;286(7):5558-66. doi: 10.1074/jbc.M110.194019. Epub 2010 Dec 28.
The Hippo pathway regulates organ size by controlling both cell proliferation and apoptosis. TAZ functions as a transcriptional co-activator downstream of the Hippo pathway and has been implicated in human cancer development. A key step in the Hippo-TAZ pathway is phosphorylation of TAZ by LATS kinase, which leads to TAZ inhibition by both cytoplasmic retention and degradation. However, the mechanism of TAZ dephosphorylation and the responsible phosphatase are unknown. Here, we identified PP1 as a bona fide TAZ phosphatase. PP1A dephosphorylates TAZ at Ser-89 and Ser-311, promotes TAZ nuclear translocation, and stabilizes TAZ by disrupting the binding to the SCF E3 ubiquitin ligase. Furthermore, ASPP2 facilitates the interaction between TAZ and PP1 to promote TAZ dephosphorylation. As a result, PP1 and ASPP2 increase TAZ-dependent gene expression. This study demonstrates that PP1A and ASPP2 play a critical role in promoting TAZ function by antagonizing the LATS kinase through TAZ dephosphorylation.
Hippo 通路通过控制细胞增殖和细胞凋亡来调节器官大小。TAZ 作为 Hippo 通路的下游转录共激活因子，与人类癌症的发展有关。Hippo-TAZ 通路的一个关键步骤是 LATS 激酶对 TAZ 的磷酸化，这导致 TAZ 通过细胞质滞留和降解而被抑制。然而，TAZ 去磷酸化的机制和负责的磷酸酶尚不清楚。在这里，我们鉴定出 PP1 是 TAZ 的一种真正的磷酸酶。PP1A 在 Ser-89 和 Ser-311 处使 TAZ 去磷酸化，促进 TAZ 核易位，并通过破坏与 SCF E3 泛素连接酶的结合来稳定 TAZ。此外，ASPP2 促进 TAZ 与 PP1 之间的相互作用，从而促进 TAZ 的去磷酸化。结果，PP1 和 ASPP2 通过 TAZ 去磷酸化来增加 TAZ 依赖性基因表达。这项研究表明，PP1A 和 ASPP2 通过 TAZ 去磷酸化拮抗 LATS 激酶，在促进 TAZ 功能方面发挥着关键作用。
