TGF-β receptor-activated p38 MAP kinase mediates smad-independent TGF-β responses
TGF-β receptor-activated p38 MAP kinase mediates smad-independent TGF-β responses
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DOI：
10.1093/emboj/cdf366
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发表时间：
2002-07-15
期刊：
影响因子：
11.4
通讯作者：
Zhang, YE
中科院分区：
文献类型：
--
作者：
Yu, L;Hébert, MC;Zhang, YE
转化生长因子- β (tgf - β)通过其膜结合I型受体的作用，引发广泛的细胞反应，调节细胞增殖、分化和凋亡。许多由tgf - β诱导的信号反应是由Smad蛋白介导的，但某些证据表明tgf - β也可以独立于Smad发出信号。我们发现，小鼠乳腺上皮细胞（NMuMG）以多种方式对tgf - β治疗有反应，tgf - β诱导的p38 MAP激酶激活是tgf - β诱导的细胞凋亡、上皮-间质转化（EMT）所必需的，但不是生长停滞。我们进一步证明了p38的激活是独立于Smads的，使用突变型I受体，它不能激活Smads，但仍然保持激酶活性。这种突变受体足以激活p38并导致NMuMG细胞发生凋亡。然而，这并不足以诱发EMT。这些结果表明，tgf - β受体信号通过多种细胞内通路传递，为smad不依赖性tgf - β受体信号的存在提供了第一手的生化证据。
Through the action of its membrane-bound type I receptors, transforming growth factor-beta (TGF-beta) elicits a wide range of cellular responses that regulate cell proliferation, differentiation and apoptosis. Many of the signaling responses induced by TGF-beta are mediated by Smad proteins, but certain evidence has suggested that TGF-beta can also signal independently of Smads. We found in mouse mammary epithelial (NMuMG) cells, which respond to TGF-beta treatment in multiple ways, that TGF-beta-induced activation of p38 MAP kinase is required for TGF-beta-induced apoptosis, epithelial-to-mesenchymal transition (EMT), but not growth arrest. We further demonstrated that activation of p38 is independent of Smads using a mutant type I receptor, which is incapable of activating Smads but still retains the kinase activity. This mutant receptor is sufficient to activate p38 and cause NMuMG cells to undergo apoptosis. However, it is not sufficient to induce EMT. These results indicate that TGF-beta receptor signals through multiple intracellular pathways and provide first-hand biochemical evidence for the existence of Smad-independent TGF-beta receptor signaling.