Liu X, Elia A E, Law S F, Golemis E A, Farley J, Wang T
Department of Surgery, Massachusetts General Hospital and Department of Genetics, Harvard Medical School, Boston, MA 02114, USA.
EMBO J. 2000 Dec 15;19(24):6759-69. doi: 10.1093/emboj/19.24.6759.
Smad3 is a key signal transducer of transforming growth factor-ss (TGF-ss) and activin, and is known to be a DNA-binding transcriptional regulator. Here we report a novel property of Smad3 in regulating the proteasomal degradation of the human enhancer of filamentation 1 (HEF1), which is a member of the Cas family of cytoplasmic docking proteins. Our studies revealed that Smad3 interacts with HEF1 and triggers the proteasomal degradation of HEF1 in overexpression systems. In addition, TGF-ss stimulation induces rapid proteasomal degradation of endogenous HEF1 in different TGF-ss-responsive cell lines. Interestingly, the degradation of HEF1 protein in epithelial cells is followed closely by an increase in HEF1 mRNA, resulting in a time-dependent increase in HEF1 protein level in TGF-ss-treated cells. Furthermore, we observed that an elevated HEF1 protein level inhibits TGF-ss-induced Smad3-mediated gene responses. These data provide the first evidence for a novel cytoplasmic activity of Smad3 in regulating proteasomal degradation of HEF1 and also suggest a role for HEF1 in a negative feedback mechanism of the TGF-ss signaling pathway.
Smad3是转化生长因子-β（TGF-β）和激活素的关键信号转导分子，并且已知是一种DNA结合转录调节因子。在此，我们报道了Smad3在调节丝状化增强子1（HEF1）的蛋白酶体降解方面的一种新特性，HEF1是细胞质对接蛋白Cas家族的成员。我们的研究表明，在过表达系统中，Smad3与HEF1相互作用并触发HEF1的蛋白酶体降解。此外，TGF-β刺激在不同的TGF-β反应性细胞系中诱导内源性HEF1的快速蛋白酶体降解。有趣的是，上皮细胞中HEF1蛋白的降解紧接着HEF1 mRNA的增加，导致TGF-β处理的细胞中HEF1蛋白水平随时间增加。此外，我们观察到升高的HEF1蛋白水平抑制TGF-β诱导的Smad3介导的基因反应。这些数据为Smad3在调节HEF1蛋白酶体降解中的新型细胞质活性提供了首个证据，并且还提示了HEF1在TGF-β信号通路的负反馈机制中的作用。
