Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis
Eya protein phosphatase activity regulates Six1-Dach-Eya transcriptional effects in mammalian organogenesis
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DOI：
10.1038/nature02083
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发表时间：
2003-11-20
期刊：
影响因子：
64.8
通讯作者：
Rosenfeld, MG
中科院分区：
文献类型：
--
作者：
Li, X;Oghi, KA;Rosenfeld, MG
基因激活和抑制事件之间的精确机制关系是哺乳动物器官发生中的一个核心问题，进化上保守的无眼（Six）、无眼（Eya）和腊肠犬（Dach）遗传相互作用蛋白网络就是例证。在这里，我们报告说，Six 1是所需的小鼠肾脏，肌肉和内耳的发展，它表现出协同遗传相互作用与Eya因子。我们证明了Eya家族具有蛋白磷酸酶功能，并且其酶活性是调节编码生长控制和信号传导分子的基因、调节前体细胞增殖所必需的。Eya的磷酸酶功能将Six 1-Dach的功能从抑制转换为激活，通过募集共激活因子引起转录激活。具有内在磷酸酶活性的共激活因子的基因特异性募集提供了用于激活特定基因靶标的分子机制，包括调节哺乳动物器官发生中的前体细胞增殖和存活的那些。
The precise mechanistic relationship between gene activation and repression events is a central question in mammalian organogenesis, as exemplified by the evolutionarily conserved sine oculis ( Six), eyes absent (Eya) and dachshund ( Dach) network of genetically interacting proteins. Here, we report that Six1 is required for the development of murine kidney, muscle and inner ear, and that it exhibits synergistic genetic interactions with Eya factors. We demonstrate that the Eya family has a protein phosphatase function, and that its enzymatic activity is required for regulating genes encoding growth control and signalling molecules, modulating precursor cell proliferation. The phosphatase function of Eya switches the function of Six1-Dach from repression to activation, causing transcriptional activation through recruitment of co-activators. The gene-specific recruitment of a co-activator with intrinsic phosphatase activity provides a molecular mechanism for activation of specific gene targets, including those regulating precursor cell proliferation and survival in mammalian organogenesis.