Receptor expression modulates the specificity of transforming growth factor-β signaling pathways
Receptor expression modulates the specificity of transforming growth factor-β signaling pathways
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DOI：
10.1111/j.1365-2443.2009.01283.x
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发表时间：
2009-04-01
期刊：
影响因子：
2.1
通讯作者：
Funaba, Masayuki
中科院分区：
文献类型：
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作者：
Murakami, Masaru;Kawachi, Hiroyuki;Funaba, Masayuki
在目前的转化生长因子- β (tgf - β)家族信号传导模型中，II型受体激活特异性激活素受体样激酶（ALK） I型受体。这些丝氨酸/苏氨酸激酶通过磷酸化羧基末端丝氨酸激活配体依赖性受体调节的(R)-Smad。我们发现受体表达水平影响两个R-Smad亚类的磷酸化和激活，激活素/ tgf - β特异性（AR-Smad）和骨形态发生蛋白（BMP）特异性（BR-Smad）。在COS7细胞中共表达组成型活性I型和II型受体导致R-Smad亚类以不依赖配体的方式磷酸化。这是通过体外激酶测定证实的。在未转染的B16黑色素瘤细胞中，tgf - β 1和BMP-2诱导R-Smad亚类磷酸化，tgf - β 1上调分化抑制因子（Id）基因，该基因通常由BMP调控。相比之下，BMP-2上调纤溶酶原激活物抑制剂-1 (PAI-1)，这是一个ar - smad调控基因。除ALK4和ALK6外，B16细胞中的I型和II型受体mrna水平高于HeLa和HepG2细胞，其中tgf - β 1和BMP-2仅诱导预期的R-Smad磷酸化。这些结果有助于解释这个配体家族的不同作用。
In current models of transforming growth factor-beta (TGF-beta) family signaling, type II receptors activate specific activin receptor-like kinase (ALK) type I receptors. These serine/threonine kinases activate ligand-dependent receptor regulated (R)-Smad by phosphorylating carboxy-terminal serines. We found that the receptor expression levels affected the phosphorylation and activation of the two R-Smad subclasses, activin/TGF-beta-specific (AR-Smad) and bone morphogenetic protein (BMP)-specific (BR-Smad). Co-expressing constitutively active type I and type II receptors in COS7 cells resulted in the phosphorylation of both R-Smad subclasses in a ligand-independent manner. This was verified using in vitro kinase assays. In untransfected B16 melanoma cells, TGF-beta 1 and BMP-2 induced phosphorylation of both R-Smad subclasses, and TGF-beta 1 up-regulated the inhibitor of differentiation (Id) gene, which is usually regulated by BMP. By contrast, BMP-2 up-regulated plasminogen activator inhibitor-1 (PAI-1), which is an AR-Smad-regulated gene. Except for ALK4 and ALK6, levels of type I and type II receptor mRNAs were higher in B16 cells than in HeLa and HepG2 cells, in which TGF-beta 1 and BMP-2 induced phosphorylation of only the expected R-Smad. These results help to explain the diverse effects of this ligand family.