Neuropilin-1 Mediates Divergent R-Smad Signaling and the Myofibroblast Phenotype
Neuropilin-1 Mediates Divergent R-Smad Signaling and the Myofibroblast Phenotype
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DOI：
10.1074/jbc.m110.151696
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发表时间：
2010-10-08
影响因子：
4.8
通讯作者：
Mukhopadhyay, Debabrata
中科院分区：
文献类型：
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作者：
Cao, Ying;Szabolcs, Annamaria;Mukhopadhyay, Debabrata
转化生长因子-β（TGF-β）超家族是最多样化的细胞信号传导途径之一，并且调节许多生理和病理过程。最近，据报道，神经纤毛蛋白-1（NRP-1）结合并激活TGF-β 1的潜伏形式（LAP-TGF-β 1）。我们研究了NRP-1对TGF-β刺激后基质成纤维细胞中Smad信号传导的作用。基质成纤维细胞系中NRP-1的消除增加了Smad 1/5磷酸化和下游反应，如分化抑制剂（Id-1）的上调所证明的。相反，NRP-1缺失降低了Smad 2/3磷酸化及其反应，如通过α-平滑肌肌动蛋白（α-SMA）的下调所示，并且细胞表现出更多的静止表型和生长停滞。此外，我们还观察到，NRP-1的表达在肝星状细胞（HSC），肝脏常驻成纤维细胞的培养活化过程中增加。总之，我们的数据表明，NRP-1作为TGF-β 1下游的不同反应的关键决定因素，这些反应由不同的Smad蛋白介导，并促进肌成纤维细胞表型。
The transforming growth factor-beta (TGF-beta) superfamily is one of the most diversified cell signaling pathways and regulates many physiological and pathological processes. Recently, neuropilin-1 (NRP-1) was reported to bind and activate the latent form of TGF-beta 1 (LAP-TGF-beta 1). We investigated the role of NRP-1 on Smad signaling in stromal fibroblasts upon TGF-beta stimulation. Elimination of NRP-1 in stromal fibroblast cell lines increases Smad1/5 phosphorylation and downstream responses as evidenced by up-regulation of inhibitor of differentiation (Id-1). Conversely, NRP-1 loss decreases Smad2/3 phosphorylation and its responses as shown by down-regulation of alpha-smooth muscle actin (alpha-SMA) and also cells exhibit more quiescent phenotypes and growth arrest. Moreover, we also observed that NRP-1 expression is increased during the culture activation of hepatic stellate cells (HSCs), a liver resident fibroblast. Taken together, our data suggest that NRP-1 functions as a key determinant of the diverse responses downstream of TGF-beta 1 that are mediated by distinct Smad proteins and promotes myofibroblast phenotype.