Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-β signaling
Endofin, a FYVE domain protein, interacts with Smad4 and facilitates transforming growth factor-β signaling
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DOI：
10.1074/jbc.m611704200
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发表时间：
2007-03-30
影响因子：
4.8
通讯作者：
Lu, Zhongxian
中科院分区：
文献类型：
--
作者：
Chen, Ye-Guang;Wang, Zhi;Lu, Zhongxian
转化生长因子-β(转化生长因子-β)信号转导受骨架蛋白如SARA(受体激活的Smad锚)的促进。Endofin是FYVE结构域蛋白家族中的一员，被认为可以调节膜转运。在这项研究中，我们报告了Enofin作为促进转化生长因子-β信号转导的支架蛋白的功能。Endofin FYVE结构域缺失突变体的过表达抑制了转化生长因子-β诱导的caga-荧光素酶的表达。RNA干扰抑制内源性内源性蛋白的表达可特异性地降低转化生长因子-β的转录反应，但对BMP或WNT1诱导的报告基因表达无影响。此外，在Endofin小干扰RNA表达稳定的细胞中，转化生长因子-β介导的纤溶酶原激活物抑制物-1和p21(Cip1)的表达显著减少，转化生长因子-β促进的细胞凋亡也受到损害。我们进一步证明，Endofin可以与Smad4和转化生长因子-βI型受体相互作用。内源性内源性蛋白表达减少导致转化生长因子-β诱导的Smad2磷酸化和Smad2-Smad4复合体形成减少。综上所述，我们的发现表明，endofin作为一种支架蛋白，通过将Smad4带到受体复合体的附近，促进R-Smad-Smad4复合体的形成，从而促进了转化生长因子-β信号转导。
Transforming growth factor-beta (TGF-beta) signaling is facilitated by scaffold proteins such as SARA (Smad anchor for receptor activation). Endofin, a member of the FYVE domain protein family, has been suggested to regulate membrane trafficking. In this study, we report that endofin functions as a scaffold protein to facilitate TGF-beta signaling. Overexpression of endofin FYVE domain-deletion mutants inhibited TGF-beta-induced expression of CAGA-luciferase. Knockdown of endogenous endofin expression by RNA interference specifically led to reduction of the transcriptional responses of TGF-beta, but had no effect on BMP-or Wnt1-induced reporter expression. Furthermore, in endofin small interfering RNA-expressing stable cells, TGF-beta-mediated expression of plasminogen activator inhibitor-1 andp21(Cip1) was significantly reduced, and TGF-beta-promoted apoptosis was also impaired. We further showed that endofin could interact with Smad4 and TGF-beta type I receptors. Reduction of endogenous endofin expression resulted in a decrease of TGF-beta-induced Smad2 phosphorylation and Smad2-Smad4 complex formation. Together, our findings suggest that endofin facilitates TGF-beta signaling as a scaffold protein to promote the R-Smad-Smad4 complex formation by bringing Smad4 to the proximity of the receptor complex.