Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation
Smad7 binds to Smurf2 to form an E3 ubiquitin ligase that targets the TGFβ receptor for degradation
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DOI：
10.1016/s1097-2765(00)00134-9
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发表时间：
2000-12-01
期刊：
影响因子：
16
通讯作者：
Wrana, JL
中科院分区：
文献类型：
--
作者：
Kavsak, P;Rasmussen, RK;Wrana, JL
泛素介导的蛋白分解调节不同受体系统的活性。在这里，我们鉴定了S-MURF2，一个C2-WW-Hect结构域的泛素连接酶，并表明S-MURF2与Smad7具有结构性联系。SMurf2是有核的，但与Smad7的结合可诱导输出和募集到激活的转化生长因子β受体，从而通过蛋白酶体和溶酶体途径导致受体和Smad7的降解。干扰素-γ刺激Smad7的表达，诱导Smad7-SMurf2复合体的形成，并增加转化生长因子β受体的转换，这种转换通过阻断Smad7或SMurf2的表达而稳定下来。此外，干扰S-MURF2向受体重新募集的Smad7突变体在其抑制活性方面也受到了影响。因此，这些研究将Smad7定义为E3泛素-连接酶复合体中的一个适配器，该复合体针对转化生长因子β受体进行降解。
Ubiquitin-mediated proteolysis regulates the activity of diverse receptor systems. Here, we identify Smurf2, a C2-WW-HECT domain ubiquitin ligase and show that Smurf2 associates constitutively with Smad7. Smurf2 is nuclear, but binding to Smad7 induces export and recruitment to the activated TGF beta receptor, where it causes degradation of receptors and Smad7 via proteasomal and lysosomal pathways. IFN gamma, which stimulates expression of Smad7, induces Smad7-Smurf2 complex formation and increases TGF beta receptor turnover, which is stabilized by blocking Smad7 or Smurf2 expression. Furthermore, Smad7 mutants that interfere with recruitment of Smurf2 to the receptors are compromised in their inhibitory activity. These studies thus define Smad7 as an adaptor in an E3 ubiquitin-ligase complex that targets the TGF beta receptor for degradation.