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孤儿配体激活素 C 通过激活素受体样激酶 7 信号传递。

The orphan ligand, activin C, signals through activin receptor-like kinase 7.

机构信息

Department of Molecular Genetics, Biochemistry, and Microbiology, University of Cincinnati, Cincinnati, United States.

Department of Pharmacology and Therapeutics, Centre for Research in Reproduction and Development, McGill University, Montreal, Canada.

出版信息

Elife. 2022 Jun 23;11:e78197. doi: 10.7554/eLife.78197.

DOI:10.7554/eLife.78197
PMID:35736809
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9224996/
Abstract

Activin ligands are formed from two disulfide-linked inhibin β (Inhβ) subunit chains. They exist as homodimeric proteins, as in the case of activin A (ActA; InhβA/InhβA) or activin C (ActC; InhβC/InhβC), or as heterodimers, as with activin AC (ActAC; InhβA:InhβC). While the biological functions of ActA and activin B (ActB) have been well characterized, little is known about the biological functions of ActC or ActAC. One thought is that the InhβC chain functions to interfere with ActA production by forming less active ActAC heterodimers. Here, we assessed and characterized the signaling capacity of ligands containing the InhβC chain. ActC and ActAC activated SMAD2/3-dependent signaling via the type I receptor, activin receptor-like kinase 7 (ALK7). Relative to ActA and ActB, ActC exhibited lower affinity for the cognate activin type II receptors and was resistant to neutralization by the extracellular antagonist, follistatin. In mature murine adipocytes, which exhibit high ALK7 expression, ActC elicited a SMAD2/3 response similar to ActB, which can also signal via ALK7. Collectively, these results establish that ActC and ActAC are active ligands that exhibit a distinct signaling receptor and antagonist profile compared to other activins.

摘要

激活素配体由两条二硫键连接的抑制素β（Inhβ）亚基链组成。它们以同源二聚体蛋白的形式存在，如激活素 A（ActA；InhβA/InhβA）或激活素 C（ActC；InhβC/InhβC），或作为异源二聚体，如激活素 AC（ActAC；InhβA:InhβC）。虽然 ActA 和激活素 B（ActB）的生物学功能已经得到很好的描述，但对 ActC 或 ActAC 的生物学功能知之甚少。一种观点认为，InhβC 链的功能是通过形成活性较低的 ActAC 异源二聚体来干扰 ActA 的产生。在这里，我们评估并表征了含有 InhβC 链的配体的信号转导能力。ActC 和 ActAC 通过 I 型受体，激活素受体样激酶 7（ALK7）激活 SMAD2/3 依赖性信号转导。与 ActA 和 ActB 相比，ActC 对同源激活素 II 型受体的亲和力较低，并且对细胞外拮抗剂 follistatin 的中和作用具有抗性。在成熟的小鼠脂肪细胞中，ALK7 表达水平较高，ActC 引发的 SMAD2/3 反应与 ActB 相似，ActB 也可以通过 ALK7 信号转导。综上所述，这些结果表明 ActC 和 ActAC 是活性配体，与其他激活素相比，它们具有独特的信号转导受体和拮抗剂特征。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/72e225e5e586/elife-78197-fig7-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/6392fbd35801/elife-78197-fig1.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/e8652071022d/elife-78197-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/5f646220f36c/elife-78197-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/e001938dd22a/elife-78197-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/0676e0654fab/elife-78197-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/3725df59a3f9/elife-78197-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/11315a89a3e3/elife-78197-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/970c8d75a93f/elife-78197-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/ebb2f6cb8622/elife-78197-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/c3d426e5e15a/elife-78197-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/58d1c3d57877/elife-78197-fig7-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/72e225e5e586/elife-78197-fig7-figsupp3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/6392fbd35801/elife-78197-fig1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/0fe28e01a56f/elife-78197-fig1-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/5d0cfde33741/elife-78197-fig2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/e8652071022d/elife-78197-fig2-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/5f646220f36c/elife-78197-fig2-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/e001938dd22a/elife-78197-fig3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/0676e0654fab/elife-78197-fig4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/3725df59a3f9/elife-78197-fig5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/11315a89a3e3/elife-78197-fig6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/970c8d75a93f/elife-78197-fig6-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/ebb2f6cb8622/elife-78197-fig7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/c3d426e5e15a/elife-78197-fig7-figsupp1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/58d1c3d57877/elife-78197-fig7-figsupp2.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/70b6/9224996/72e225e5e586/elife-78197-fig7-figsupp3.jpg

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