An Activin/Furin Regulatory Loop Modulates the Processing and Secretion of Inhibin α- and βB-Subunit Dimers in Pituitary Gonadotrope Cells
An Activin/Furin Regulatory Loop Modulates the Processing and Secretion of Inhibin α- and βB-Subunit Dimers in Pituitary Gonadotrope Cells
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DOI：
10.1074/jbc.m804190200
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发表时间：
2008-11-28
影响因子：
4.8
通讯作者：
Woodruff, Teresa K.
中科院分区：
文献类型：
--
作者：
Antenos, Monica;Zhu, Jie;Woodruff, Teresa K.
在转化生长因子β超家族的所有配体中，抑制素和激活素是一对生理上相关的相互作用的拮抗剂。激活素刺激促性腺激素的生物合成和分泌，而抑制素抑制促性腺激素的生物合成和分泌，抑制素和激活素共同控制对正常生殖功能至关重要的垂体性腺轴。作为成熟的生物活性配体，抑制素异二聚体(α/β)或激活素同源二聚体(β/β)的分泌共享相似的β亚基，这在一定程度上取决于前体蛋白的蛋白分解过程。发现了一条控制前体加工和二聚体分泌的短环调控通路。激活素刺激内源性抑制素α和β(B)亚单位的mRNA、蛋白质和蛋白降解过程。同时，激活素通过Smad2/3依赖的过程刺激原转化酶Furin。这些数据提供了一种机制，其中呋喃和抑制素亚单位的调节在一个重要的正向短反馈环路中协同工作。这个调节环路增加了生物活性成熟激活素B和抑制素B二聚体的分泌，这是局部卵泡刺激素β调节所必需的。
Of all ligands of the transforming growth factor beta superfamily, inhibins and activins are a physiologically relevant pair that are functional antagonists of each other. Activin stimulates whereas inhibin blocks follicle-stimulating hormone biosynthesis and secretion from pituitary gonadotrope cells, and together, inhibin and activin control the pituitary gonadal axis essential for normal reproductive function. Sharing a similar beta-subunit, the secretion of inhibin heterodimers (alpha/beta) or activin homodimers (beta/beta) as mature bioactive ligands depends, in part, on the proteolytic processing of precursor proteins. A short loop regulatory pathway controlling precursor processing and dimer secretion was discovered. Activin stimulates endogenous inhibin alpha- and beta(B)-subunit mRNA, protein, and proteolytic processing. Simultaneously, activin stimulated the proconvertase furin through a Smad2/3-dependent process. The data provide a mechanism where the regulation of furin and inhibin subunits cooperates in an important positive short feedback loop. This regulatory loop augments the secretion of bioactive mature activin B, as well as inhibin B dimers, necessary for local follicle-stimulating hormone beta regulation.