The orphan ligand, activin C, signals through activin receptor-like kinase 7
The orphan ligand, activin C, signals through activin receptor-like kinase 7
复制标题
DOI：
10.1101/2022.03.16.484571
复制
发表时间：
2022-03
期刊：
影响因子：
7.7
通讯作者：
Erich J. Goebel;Luisina Ongaro;Emily C Kappes;Elitza Belcheva;R. Castonguay;Ravindra Kumar;D. Bernard;T. Thompson
中科院分区：
文献类型：
--
作者：
Erich J. Goebel;Luisina Ongaro;Emily C Kappes;Elitza Belcheva;R. Castonguay;Ravindra Kumar;D. Bernard;T. Thompson
激活素配体由两个二硫键连接的腺苷酸β亚基链形成。它们以同二聚体蛋白存在，如激活素A（ActA; InhβA/InhβA）或激活素C（ActC; InhβC/InhβC）的情况，或以异二聚体存在，如激活素AC（ActAC; InhβA：InhβC）的情况。虽然ActA和激活素B（ActB）的生物学功能已被充分表征，但对ActC或ActAC的生物学功能知之甚少。一种想法是InhβC链通过形成活性较低的ActAC异二聚体来干扰ActA的产生。在这里，我们评估并表征了含有InhβC链的配体的信号传导能力。ActC和ActAC通过I型受体激活素受体样激酶7（ALK 7）激活SMAD 2/3依赖性信号传导。相对于ActA和ActB，ActC对同源激活素II型受体表现出较低的亲和力，并且对细胞外拮抗剂卵泡抑素的中和具有抗性。在表现出高ALK 7表达的成熟脂肪细胞中，ActC引发了与ActB类似的SMAD 2/3反应，ActB也可以通过ALK 7发出信号。总的来说，这些结果确定了ActC和ActAC是活性配体，与其他激活素相比，其表现出不同的信号传导受体和拮抗剂谱。
Activin ligands are formed from two disulfide-linked inhibin β 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 function 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 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.