Activins bind and signal via bone morphogenetic protein receptor type II (BMPR2) in immortalized gonadotrope-like cells
Activins bind and signal via bone morphogenetic protein receptor type II (BMPR2) in immortalized gonadotrope-like cells
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DOI：
10.1016/j.cellsig.2013.09.002
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发表时间：
2013-12-01
影响因子：
4.8
通讯作者：
Bernard, Daniel J.
中科院分区：
文献类型：
--
作者：
Rejon, Carlis A.;Hancock, Mark A.;Bernard, Daniel J.
TGF β超家族配体的数量远远超过它们的受体。因此，受体在配体之间是共享的，单个配体可以结合多个受体。骨形态发生蛋白（BMPs）通过BMP II型（BMPR2）和激活素II型（ACVR2）受体结合并发出信号。我们假设，除了它的典型受体ACVR2，激活素A可能同样通过BMPR2结合并发出信号。首先，利用表面等离子体共振，我们发现激活素A与BMPR2细胞外结构域（ECD）结合，尽管与ACVR2-ECD相比亲和力较低。我们在细胞中证实了这些结果，其中放射性标记的激活素A与ACVR2和BMPR2结合，但不与其他II型受体（AMHR2或TGFBR2）结合。通过同源性建模和位点定向诱变，我们确定了BMPR2中介导其与激活素A相互作用的关键残基。ACVR2或BMPR2的可溶性ECDs可以剂量依赖性地抑制激活素A-，但不能抑制细胞中TGF β诱导的信号传导，这表明激活素与BMPR2结合可能具有功能后果。为了解决这个问题，我们改变了永生化小鼠促性腺激素样细胞L β T2中的BMPR2表达水平，其中激活素可以有效地刺激促卵泡激素β (Fshb)亚基转录。BMPR2的表达增强了激活素A的反应，而用短干扰rna耗尽内源性BMPR2则减弱了激活素A刺激的Fshb转录。其他数据首次表明，BMPR2可能与典型激活素I型受体（激活素受体样激酶4）形成功能复合物。总的来说，我们的数据表明，BMPR2和ACVR2在促性腺激素样细胞中作为真正的激活素II型受体发挥作用，从而拓宽了我们对激活素作用机制的理解。(C) 2013爱思唯尔公司版权所有。
TGF beta superfamily ligands greatly outnumber their receptors. Thus, receptors are shared between ligands and individual ligands can bind multiple receptors. Bone morphogenetic proteins (BMPs) bind and signal via both BMP type II (BMPR2) and activin type II (ACVR2) receptors. We hypothesized that, in addition to its canonical receptor ACVR2, activin A might similarly bind and signal via BMPR2. First, using surface plasmon resonance, we showed that activin A binds to the BMPR2 extracellular domain (ECD), though with lower affinity compared to the ACVR2-ECD. We confirmed these results in cells, where radiolabeled activin A bound to ACVR2 and BMPR2, but not to other type II receptors (AMHR2 or TGFBR2). Using homology modeling and site-directed mutagenesis, we identified key residues in BMPR2 that mediate its interaction with activin A. The soluble ECDs of ACVR2 or BMPR2 dose-dependently inhibited activin A-, but not TGF beta-induced signaling in cells, suggesting that activin binding to BMPR2 could have functional consequences. To address this idea, we altered BMPR2 expression levels in immortalized murine gonadotrope-like cells, L beta T2, in which activins potently stimulate follicle-stimulating hormone beta (Fshb) subunit transcription. BMPR2 expression potentiated activin A responses whereas depletion of endogenous BMPR2 with short interfering RNAs attenuated activin A-stimulated Fshb transcription. Additional data suggest, for the first time, that BMPR2 may form functional complexes with the canonical activin type I receptor, activin receptor-like kinase 4. Collectively, our data show that BMPR2, along with ACVR2, functions as a bona fide activin type II receptor in gonadotrope-like cells, thereby broadening our understanding of mechanisms of activin action. (C) 2013 Elsevier Inc. All rights reserved.