He Wei, Dorn David C, Erdjument-Bromage Hediye, Tempst Paul, Moore Malcolm A S, Massagué Joan
Cancer Biology and Genetics Program and Howard Hughes Medical Institute, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
Cell. 2006 Jun 2;125(5):929-41. doi: 10.1016/j.cell.2006.03.045.
Tissue homeostasis in mammals relies on powerful cytostatic and differentiation signals delivered by the cytokine TGFbeta and relayed within the cell via the activation of Smad transcription factors. Formation of transcription regulatory complexes by the association of Smad4 with receptor-phosphorylated Smads 2 and 3 is a central event in the canonical TGFbeta pathway. Here we provide evidence for a branching of this pathway. The ubiquitious nuclear protein Transcriptional Intermediary Factor 1gamma (TIF1gamma) selectively binds receptor-phosphorylated Smad2/3 in competition with Smad4. Rapid and robust binding of TIF1gamma to Smad2/3 occurs in hematopoietic, mesenchymal, and epithelial cell types in response to TGFbeta. In human hematopoietic stem/progenitor cells, where TGFbeta inhibits proliferation and stimulates erythroid differentiation, TIF1gamma mediates the differentiation response while Smad4 mediates the antiproliferative response with Smad2/3 participating in both responses. Thus, Smad2/3-TIF1gamma and Smad2/3-Smad4 function as complementary effector arms in the control of hematopoietic cell fate by the TGFbeta/Smad pathway.
哺乳动物的组织稳态依赖于细胞因子转化生长因子β（TGFβ）传递的强大的细胞生长抑制和分化信号，这些信号通过Smad转录因子的激活在细胞内传递。Smad4与受体磷酸化的Smad2和Smad3结合形成转录调节复合物是经典TGFβ信号通路中的核心事件。在此，我们提供了该信号通路分支的证据。普遍存在的核蛋白转录中介因子1γ（TIF1γ）与Smad4竞争，选择性地结合受体磷酸化的Smad2/3。响应TGFβ，TIF1γ与Smad2/3在造血、间充质和上皮细胞类型中发生快速而强烈的结合。在人类造血干/祖细胞中，TGFβ抑制增殖并刺激红系分化，TIF1γ介导分化反应，而Smad4介导抗增殖反应，Smad2/3参与这两种反应。因此，在TGFβ/Smad信号通路控制造血细胞命运的过程中，Smad2/3-TIF1γ和Smad2/3-Smad4作为互补的效应臂发挥作用。
