Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3.
Cross-talk between the Notch and TGF-beta signaling pathways mediated by interaction of the Notch intracellular domain with Smad3.
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Notch 和 TGF-β 信号通路之间的串扰由 Notch 胞内结构域与 Smad3 的相互作用介导。
DOI：
10.1083/jcb.200305112
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发表时间：
2003-11-24
影响因子：
7.8
通讯作者：
Ibáñez, CF
中科院分区：
文献类型：
--
作者：
Blokzijl, A;Dahlqvist, C;Reissmann, E;Falk, A;Moliner, A;Lendahl, U;Ibáñez, CF
Notch和转化生长因子-β（transforming growth factor-β，TGF-β）信号通路在后生动物发育过程中对细胞命运的控制起着关键作用。然而，这两个系统之间的串扰和信号集成的机制是未知的。在这里，我们证明了Notch和TGF-β信号转导在调节Hes-1（Notch途径的直接靶点）中的功能协同作用。TGF-β信号的激活在体外和体内上调Hes-1的表达。这种效应在肌原性细胞中被显性阴性形式的CSL消除，CSL是Notch途径的一种重要DNA结合组分。TGF-β以Notch依赖的方式调节Hes-1启动子的转录，Notch 1的胞内结构域（NICD）与TGF-β信号的胞内转导子Smad 3协同作用，诱导含有多聚化CSL或Smad 3结合位点的合成启动子的活化。NICD和Smad 3在体外和细胞中以配体依赖性方式直接相互作用，并且Smad 3可以在CSL和NICD存在下被募集到DNA上的CSL结合位点。这些发现表明，Notch和TGF-β信号通过来自两种途径的信号转导细胞内元件之间的直接蛋白质-蛋白质相互作用来整合。
The Notch and transforming growth factor-β (TGF-β) signaling pathways play critical roles in the control of cell fate during metazoan development. However, mechanisms of cross-talk and signal integration between the two systems are unknown. Here, we demonstrate a functional synergism between Notch and TGF-β signaling in the regulation of Hes-1, a direct target of the Notch pathway. Activation of TGF-β signaling up-regulated Hes-1 expression in vitro and in vivo. This effect was abrogated in myogenic cells by a dominant-negative form of CSL, an essential DNA-binding component of the Notch pathway. TGF-β regulated transcription from the Hes-1 promoter in a Notch-dependent manner, and the intracellular domain of Notch1 (NICD) cooperated synergistically with Smad3, an intracellular transducer of TGF-β signals, to induce the activation of synthetic promoters containing multimerized CSL- or Smad3-binding sites. NICD and Smad3 were shown to interact directly, both in vitro and in cells, in a ligand-dependent manner, and Smad3 could be recruited to CSL-binding sites on DNA in the presence of CSL and NICD. These findings indicate that Notch and TGF-β signals are integrated by direct protein–protein interactions between the signal-transducing intracellular elements from both pathways.
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影响因子：
9.2
作者：
Blokzijl, A;ten Dijke, P;Ibáñez, CF
通讯作者：
Ibáñez, CF
影响因子：
11.4
作者：
Goumans, MJ;Valdimarsdottir, G;ten Dijke, P
通讯作者：
ten Dijke, P
影响因子：
64.8
作者：
JARRIAULT, S;BROU, C;ISRAEL, A
通讯作者：
ISRAEL, A
影响因子：
10.5
作者：
Liu, D;Black, BL;Derynck, R
通讯作者：
Derynck, R
影响因子：
64.5
作者：
Palmeirim, I;Henrique, D;Pourquie, O
通讯作者：
Pourquie, O