Department of Molecular and Cellular Biosciences, University of Cincinnati, Cincinnati, OH 45267, U.S.A.
Department of Pharmacology and Therapeutics, Centre for Research in Reproduction and Development, McGill University, Montreal, Quebec, Canada.
Biochem J. 2024 Apr 10;481(7):547-564. doi: 10.1042/BCJ20230404.
Activins are one of the three distinct subclasses within the greater Transforming growth factor β (TGFβ) superfamily. First discovered for their critical roles in reproductive biology, activins have since been shown to alter cellular differentiation and proliferation. At present, members of the activin subclass include activin A (ActA), ActB, ActC, ActE, and the more distant members myostatin and GDF11. While the biological roles and signaling mechanisms of most activins class members have been well-studied, the signaling potential of ActE has remained largely unknown. Here, we characterized the signaling capacity of homodimeric ActE. Molecular modeling of the ligand:receptor complexes showed that ActC and ActE shared high similarity in both the type I and type II receptor binding epitopes. ActE signaled specifically through ALK7, utilized the canonical activin type II receptors, ActRIIA and ActRIIB, and was resistant to the extracellular antagonists follistatin and WFIKKN. In mature murine adipocytes, ActE invoked a SMAD2/3 response via ALK7, like ActC. Collectively, our results establish ActE as a specific signaling ligand which activates the type I receptor, ALK7.
激活素是转化生长因子 β（TGFβ）超家族中三个不同亚类之一。最初发现其在生殖生物学中的关键作用，激活素已被证明可以改变细胞分化和增殖。目前，激活素亚类的成员包括激活素 A（ActA）、ActB、ActC、ActE 以及更远的成员肌肉生长抑制素和 GDF11。虽然大多数激活素类成员的生物学作用和信号机制已经得到很好的研究，但 ActE 的信号潜力仍然知之甚少。在这里，我们描述了同源二聚体 ActE 的信号转导能力。配体：受体复合物的分子建模表明，ActC 和 ActE 在 I 型和 II 型受体结合表位都具有高度相似性。ActE 通过 ALK7 特异性信号转导，利用经典的激活素 II 型受体 ActRIIA 和 ActRIIB，并且对细胞外拮抗剂 follistatin 和 WFIKKN 具有抗性。在成熟的小鼠脂肪细胞中，ActE 通过 ALK7 引发 SMAD2/3 反应，与 ActC 相似。总之，我们的结果确立了 ActE 作为一种特定的信号配体，可激活 I 型受体 ALK7。
