A Smad action turnover switch operated by WW domain readers of a phosphoserine code
A Smad action turnover switch operated by WW domain readers of a phosphoserine code
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DOI：
10.1101/gad.2060811
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发表时间：
2011-06-15
影响因子：
10.5
通讯作者：
Macias, Maria J.
中科院分区：
文献类型：
--
作者：
Aragon, Eric;Goerner, Nina;Macias, Maria J.
当通过TGF-β或BMP信号将其定向到核时，SMAD蛋白会经历细胞周期蛋白依赖性激酶8/9（CDK8/9）和糖原合酶激酶3（GSK3）磷酸化，这些磷酸化介导YAP和PIN1的结合，转录作用，以及用于SMAD破坏的泛素连接酶Smurf1和Nedd4L的作品。在这里，我们证明，首先有事件弹性激活的顺序，后来又破坏了它，并且由WW域在其结合伙伴中识别smad磷se的开关控制。在BMP途径中，CDK8/9的SMAD1磷酸化为YAP的WW结构域创建结合位点，而GSK3随后磷酸化会关闭YAP结合，并为SMURF1 WW域添加结合位点。同样，在TGF-β途径中，CDK8/9的SMAD3磷酸化为PIN1和GSK3创建结合位点，然后添加位点以增强NEDD4L结合。因此，SMAD磷s码代码和一组WW域代码读取器为将TGF-beta信号传递耦合到SMAD信号传感器的营业额提供了有效的解决方案。
When directed to the nucleus by TGF-beta or BMP signals, Smad proteins undergo cyclin-dependent kinase 8/9 (CDK8/9) and glycogen synthase kinase-3 (GSK3) phosphorylations that mediate the binding of YAP and Pin1 for transcriptional action, and of ubiquitin ligases Smurf1 and Nedd4L for Smad destruction. Here we demonstrate that there is an order of events-Smad activation first and destruction later-and that it is controlled by a switch in the recognition of Smad phosphoserines by WW domains in their binding partners. In the BMP pathway, Smad1 phosphorylation by CDK8/9 creates binding sites for the WW domains of YAP, and subsequent phosphorylation by GSK3 switches off YAP binding and adds binding sites for Smurf1 WW domains. Similarly, in the TGF-beta pathway, Smad3 phosphorylation by CDK8/9 creates binding sites for Pin1 and GSK3, then adds sites to enhance Nedd4L binding. Thus, a Smad phosphoserine code and a set of WW domain code readers provide an efficient solution to the problem of coupling TGF-beta signal delivery to turnover of the Smad signal transducers.