Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation
Activin and inhibin have antagonistic effects on ligand-dependent heteromerization of the type I and type II activin receptors and human erythroid differentiation
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DOI：
10.1128/mcb.17.3.1682
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发表时间：
1997-03-01
影响因子：
5.3
通讯作者：
Vale, WW
中科院分区：
文献类型：
--
作者：
Lebrun, JJ;Vale, WW
激活素和抑制素属于转化生长因子 β (TGF-β) 样超家族，通过调节细胞分化和增殖对广泛的细胞靶标发挥作用。该家族的成员与两类结构相关的受体（I 型和 II 型）相互作用，两者都含有丝氨酸/苏氨酸激酶结构域。当单独表达时，II 型激活素受体（而不是 I 型激活素受体）可以结合激活素，但是，信号传导需要 I 型受体的存在。对于TGF-β1，配体与II型受体结合导致I型受体的募集和转磷酸化，两种类型的激活素受体的瞬时过度表达导致配体独立的受体异聚化和激活，然而，转染细胞中的激活素增加了两种受体之间的复合物形成，表明与观察到的TGF-β受体相似的作用机制。在本研究中，我们产生了稳定的细胞系，过度表达两种类型的激活素受体在人红白血病细胞系 K562 中诱导后，我们在此证明激活素以时间依赖性方式特异性诱导 I 型和 II 型受体之间的异聚体形成。使用该稳定细胞系，我们分析了激活素和抑制素对人红细胞分化的影响。我们的结果表明，通过其 I 型和 II 型受体介导的激活素信号转导导致细胞血红蛋白含量增加并限制其增殖。最后，使用可被诱导过度表达 ActRII 和 ActRIB 或仅 ActRIB 的细胞系，我们表明抑制素对激活素诱导的生物反应的拮抗作用是通过竞争 II 型激活素受体介导的，但也需要存在抑制素特异性结合成分。
Activins and inhibins belong to the transforming growth factor beta (TGF-beta)-like superfamily and exert their effects on a broad range of cellular targets by modulating cell differentiation and proliferation. Members of this family interact with two structurally related classes of receptors (type I and type II), both containing a serine/threonine kinase domain, When expressed alone, the type II but not the type I activin receptor can bind activin, However, the presence of a type I receptor is required for signaling. For TGF-beta 1, ligand binding to the type II receptor results in the recruitment and transphosphorylation of the type I receptor, Transient overexpression of the two types of activin receptor results in ligand-independent receptor heteromerization and activation, Nevertheless, activin addition to the transfected cells increased complex formation between the two receptors, suggesting a mechanism of action similar to that observed for the TGF-beta receptor, In the present study, we generated a stable cell line, overexpressing the two types of activin receptor upon induction, in the human erythroleukemia cell line K562, We demonstrate here that activin specifically induces heteromer formation between the type I and type II receptors in a time-dependent manner, Using this stable line, we analysed the effects of activin and inhibin on human erythroid differentiation. Our results indicate that activin signal transduction mediated through its type I and type II receptors results in an increase in the hemoglobin content of the cells and limits their proliferation. Finally, using cell lines that can be induced to overexpress ActRII and ActRIB or ActRIB only, we show that the inhibin antagonistic effects on activin-induced biological responses are mediated through a competition for the type II activin receptor but also require the presence of an inhibin-specific binding component.