Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling
Yes-associated protein (YAP65) interacts with Smad7 and potentiates its inhibitory activity against TGF-β/Smad signaling
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DOI：
10.1038/sj.onc.1205623
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发表时间：
2002-07-25
期刊：
影响因子：
8
通讯作者：
Mauviel, A
中科院分区：
文献类型：
--
作者：
Ferrigno, O;Lallemand, F;Mauviel, A
生长因子的TGF-β家族的成员通过丝氨酸/苏氨酸激酶受体从细胞表面发出信号。信号的细胞内传播通过Smad家族的细胞内蛋白质的磷酸化而发生。Smad 7属于抑制性Smads的亚类，其作为TGF-β信号传导的拮抗剂起作用。使用全长小鼠Smad 7作为诱饵，对人胎盘cDNA表达文库进行酵母双杂交筛选，鉴定出Yes-Associated Protein（YAP 65）是一种新型Smad 7相互作用蛋白。使用COS-7细胞中共表达的标记蛋白证实Smad 7与YAP 65的缔合。Smad 7的PY基序的缺失减少，但没有取消YAP 65-Smad 7协会，这表明存在几个相互作用的结构域。我们证明，YAP 65增强了Smad 7对TGF-β诱导的Smad 3/4依赖性基因反式激活的抑制活性。此外，YAP 65增强Smad 7与活化的TGF-β受体I型（TbetaRI）的结合，而YAP 65（1-301）对Smad 7驱动的TGF-β信号传导抑制发挥显性负效应，减少这些相互作用。总之，这些数据提供了第一个证据，即YAP 65是Smad 7伴侣，促进后者向活化的TbetaRI的募集，并增强Smad 7对TGF-β信号传导的抑制活性。
Members of the TGF-beta family of growth factors signal from the cell surface through serine/threonine kinase receptors. Intracellular propagation of the signal occurs by phosphorylation of intracellular proteins of the Smad family. Smad7 belongs to the subclass of inhibitory Smads that function as antagonists of TGF-beta signaling. A yeast two-hybrid screen of a human placental cDNA expression library using full-length mouse Smad7 as bait identified Yes-Associated Protein (YAP65) as a novel Smad7-interacting protein. The association of Smad7 with YAP65 was confirmed using co-expressed tagged proteins in COS-7 cells. Deletion of the PY motif of Smad7 reduced but did not abolish YAP65-Smad7 association, suggesting the existence of several interacting domains. We demonstrate that YAP65 potentiates the inhibitory activity of Smad7 against TGF-beta-induced, Smad3/4-dependent, gene transactivation. Furthermore, YAP65 augments the association of Smad7 to activated TGF-beta receptor type I (TbetaRI), whereas YAP65(1-301), which exerts a dominant-negative effect against Smad7-driven inhibition of TGF-beta signaling, reduces these interactions. Together, these data provide the first evidence that YAP65 is a Smad7 partner that facilitates the recruitment of the latter to activated TbetaRI, and enhances the inhibitory activity of Smad7 against TGF-beta signaling.