PPM1A functions as a Smad phosphatase to terminate TGFβ signaling (Publication with Expression of Concern. See vol. 166, 2016) (Publication with Expression of Concern. See vol. 165, pg. 498, 2016)
PPM1A functions as a Smad phosphatase to terminate TGFβ signaling (Publication with Expression of Concern. See vol. 166, 2016) (Publication with Expression of Concern. See vol. 165, pg. 498, 2016)
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DOI：
10.1016/j.cell.2006.03.044
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发表时间：
2006-06-02
期刊：
影响因子：
64.5
通讯作者：
Feng, Xin-Hua
中科院分区：
文献类型：
--
作者：
Lin, Xia;Duan, Xueyan;Feng, Xin-Hua
TGFβ信号控制疾病，包括癌症，自身免疫性和纤维化疾病在内的疾病的各种正常发育过程和发病机理。 TGFβ响应通常是通过SMADS的转录函数介导的。 TGF Beta信号传导的关键步骤是配体诱导的受体激活SMADS（R-SMADS）由TGFβ型I型受体激酶催化的受体激活SMADS（R-SMADS）。但是，Smad去磷酸化作为TGFβ信号传导的调节机制和SMAD特异性磷酸酶的身份的潜力仍然难以捉摸。使用功能性基因组方法，我们将PPM1A/PP2Cα鉴定为真正的SMAD磷酸酶。 PPM1A去磷酸化并促进TGF Beta激活SMAD2/3的核出口。 PPM1A的异位表达废除了TGFβ诱导的抗增殖和转录反应，而PPM1A的耗竭增强了哺乳动物细胞中TGFβ信号传导。在斑马鱼中淋巴结依赖性的早期胚胎发生过程中，还观察到了PPM1A的Smad抗抗酸活性。这项工作表明，通过SMAD2/3的去磷酸化，PPM1A/PP2Cα在终止TGFβ信号传导中起着至关重要的作用。
TGF beta signaling controls diverse normal developmental processes and pathogenesis of diseases including cancer and autoimmune and fibrotic diseases. TGF beta responses are generally mediated through transcriptional functions of Smads. A key step in TGF beta signaling is ligand-induced phosphorylation of receptor-activated Smads (R-Smads) catalyzed by the TGF beta type I receptor kinase. However, the potential of Smad dephosphorylation as a regulatory mechanism of TGF beta signaling and the identity of Smad-specific phosphatases remain elusive. Using a functional genomic approach, we have identified PPM1A/PP2C alpha as a bona fide Smad phosphatase. PPM1A dephosphorylates and promotes nuclear export of TGF beta-activated Smad2/3. Ectopic expression of PPM1A abolishes TGF beta-induced anti proliferative and transcriptional responses, whereas depletion of PPM1A enhances TGF beta signaling in mammalian cells. Smad-antagonizing activity of PPM1A is also observed during Nodal-dependent early embryogenesis in zebrafish. This work demonstrates that PPM1A/PP2C alpha, through dephosphorylation of Smad2/3, plays a critical role in terminating TGF beta signaling.