Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins
Biological activity of follistatin isoforms and follistatin-like-3 is dependent on differential cell surface binding and specificity for activin, myostatin, and bone morphogenetic proteins
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DOI：
10.1210/en.2006-0089
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发表时间：
2006-07-01
期刊：
影响因子：
4.8
通讯作者：
Schneyer, Alan
中科院分区：
文献类型：
--
作者：
Sidis, Yisrael;Mukherjee, Abir;Schneyer, Alan
卵泡抑素（FST）和FST样-3（FSTL 3）是也结合肌生长抑制素的激活素结合和中和蛋白。已经描述了三种FST亚型，它们在组织分布和细胞表面结合活性上不同，这表明FST亚型和FSTL 3可能具有一些不重叠的生物学作用。我们生产了重组FST异构体和FSTL 3，并比较了它们的生化和生物学特性。激活素结合亲和力和动力学在同种型和FSTL 3之间是相当的，而细胞表面结合显著不同（FST 288> FST 303> FST 315> FSTL 3）。内源性激活素生物活性的抑制，无论FST亚型是内源性还是外源性施用，都与表面结合活性密切相关，而当FST和FSTL 3也是外源性时，外源性激活素的中和与它们的等效激活素结合亲和力一致。这种激活素抑制的差异在体外生物测定中也很明显，因为FST 288抑制激活素依赖性TT细胞增殖，而FST 315增强激活素依赖性TT细胞增殖。此外，当不与细胞膜结合的FSTL 3表达为膜锚定蛋白时，其内源性激活素抑制活性显著增加。在竞争性结合试验中，肌生长抑制素比骨形态发生蛋白（BMP）6和7更有效，BMP 2和4在与FST同种型的结合中无活性，而测试的BMP均不与激活素竞争与FSTL 3的结合。中和外源性BMP或肌生长抑制素的生物活性与同种型结合细胞表面蛋白聚糖的相对能力相关。这些结果表明，FST亚型和FSTL 3之间的差异生物学作用主要取决于它们的相对细胞表面结合能力和配体特异性。
Follistatin (FST) and FST-like-3 (FSTL3) are activin-binding and neutralization proteins that also bind myostatin. Three FST isoforms have been described that differ in tissue distribution and cell-surface binding activity, suggesting that the FST isoforms and FSTL3 may have some nonoverlapping biological actions. We produced recombinant FST isoforms and FSTL3 and compared their biochemical and biological properties. Activin-binding affinities and kinetics were comparable between the isoforms and FSTL3, whereas cell-surface binding differed markedly (FST288 > FST303 > FST315 > FSTL3). Inhibition of endogenous activin bioactivity, whether the FST isoforms were administered endogenously or exogenously, correlated closely with surface binding activity, whereas neutralization of exogenous activin when FST and FSTL3 were also exogenous was consistent with their equivalent activin-binding affinities. This difference in activin inhibition was also evident in an in vitro bioassay because FST288 suppressed, whereas FST315 enhanced, activin-dependent TT cell proliferation. Moreover, when FSTL3, which does not associate with cell membranes, was expressed as a membrane-anchored protein, its endogenous activin inhibitory activity was dramatically increased. In competitive binding assays, myostatin was more potent than bone morphogenetic proteins (BMPs) 6 and 7, and BMPs 2 and 4 were inactive in binding to FST isoforms, whereas none of the BMPs tested competed with activin for binding to FSTL3. Neutralization of exogenous BMP or myostatin bioactivity correlated with the relative abilities of the isoforms to bind cell-surface proteoglycans. These results indicate that the differential biological actions among the FST isoforms and FSTL3 are primarily dependent on their relative cell-surface binding ability and ligand specificity.