Lei Qun-Ying, Zhang Heng, Zhao Bin, Zha Zheng-Yu, Bai Feng, Pei Xin-Hai, Zhao Shimin, Xiong Yue, Guan Kun-Liang
Department of Biological Chemistry, School of Medicine, Molecular and Cellular Biology Laboratory, Institutes of Biomedical Sciences, Department of Biology, School of Life Science, Fudan University, Shanghai 200032, China.
Mol Cell Biol. 2008 Apr;28(7):2426-36. doi: 10.1128/MCB.01874-07. Epub 2008 Jan 28.
TAZ is a WW domain containing a transcription coactivator that modulates mesenchymal differentiation and development of multiple organs. In this study, we show that TAZ is phosphorylated by the Lats tumor suppressor kinase, a key component of the Hippo pathway, whose alterations result in organ and tissue hypertrophy in Drosophila and contribute to tumorigenesis in humans. Lats phosphorylates TAZ on several serine residues in the conserved HXRXXS motif and creates 14-3-3 binding sites, leading to cytoplasmic retention and functional inactivation of TAZ. Ectopic expression of TAZ stimulates cell proliferation, reduces cell contact inhibition, and promotes epithelial-mesenchymal transition (EMT). Elimination of the Lats phosphorylation sites results in a constitutively active TAZ, enhancing the activity of TAZ in promoting cell proliferation and EMT. Our results elucidate a molecular mechanism for TAZ regulation and indicate a potential function of TAZ as an important target of the Hippo pathway in regulating cell proliferation tumorigenesis.
TAZ是一种含有WW结构域的转录共激活因子，可调节间充质分化和多个器官的发育。在本研究中，我们发现TAZ被Lats肿瘤抑制激酶磷酸化，Lats肿瘤抑制激酶是Hippo信号通路的关键组成部分，其改变会导致果蝇的器官和组织肥大，并促进人类肿瘤发生。Lats在保守的HXRXXS基序中的几个丝氨酸残基上使TAZ磷酸化，并产生14-3-3结合位点，导致TAZ在细胞质中滞留并使其功能失活。TAZ的异位表达刺激细胞增殖，降低细胞接触抑制，并促进上皮-间质转化（EMT）。消除Lats磷酸化位点会产生组成型激活的TAZ，增强TAZ促进细胞增殖和EMT的活性。我们的结果阐明了TAZ调节的分子机制，并表明TAZ作为Hippo信号通路在调节细胞增殖和肿瘤发生中的重要靶点的潜在功能。
