TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway
TAZ promotes cell proliferation and epithelial-mesenchymal transition and is inhibited by the hippo pathway
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TAZ 促进细胞增殖和上皮间质转化，并受 hippo 通路抑制
DOI：
10.1128/mcb.01874-07
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发表时间：
2008-04-01
影响因子：
5.3
通讯作者：
Guan, Kun-Liang
中科院分区：
文献类型：
--
作者：
Lei, Qun-Ying;Zhang, Heng;Guan, Kun-Liang
TAZ是一个含有转录辅激活因子的WW结构域，可调节多器官间质分化和发育。在这项研究中，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通路的一个关键组成部分，其改变导致果蝇的器官和组织肥大，并有助于人类的肿瘤发生。Lats磷酸化保守的HXRXXS基序中几个丝氨酸残基上的TAZ，并产生14-3-3结合位点，导致细胞质保留和TAZ的功能失活。异位表达TAZ刺激细胞增殖，减少细胞接触抑制，促进上皮-间质转化（EMT）。Lats磷酸化位点的消除导致TAZ的组成活性，增强TAZ在促进细胞增殖和EMT中的活性。我们的研究结果阐明了TAZ调控的分子机制，并表明TAZ作为Hippo通路调控细胞增殖肿瘤发生的重要靶点的潜在功能。
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.