Tsuchida Kunihiro, Nakatani Masashi, Uezumi Akiyoshi, Murakami Tatsuya, Cui Xueling
Division for Therapies against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi, Japan.
Endocr J. 2008 Mar;55(1):11-21. doi: 10.1507/endocrj.kr-110. Epub 2007 Sep 14.
Activin, myostatin and other members of the TGF-beta superfamily signal through a combination of type II and type I receptors, both of which are transmembrane serine/threonine kinases. Activin type II receptors, ActRIIA and ActRIIB, are primary ligand binding receptors for activins, nodal, myostatin and GDF11. ActRIIs also bind a subset of bone morphogenetic proteins (BMPs). Type I receptors that form complexes with ActRIIs are dependent on ligands. In the case of activins and nodal, activin receptor-like kinases 4 and 7 (ALK4 and ALK7) are the authentic type I receptors. Myostatin and GDF11 utilize ALK5, although ALK4 could also be activated by these growth factors. ALK4, 5 and 7 are structurally and functionally similar and activate receptor-regulated Smads for TGF-beta, Smad2 and 3. BMPs signal through a combination of three type II receptors, BMPRII, ActRIIA, and ActRIIB and four type I receptors, ALK1, 2, 3, and 6. BMPs activate BMP-specific Smads, Smad1, 5 and 8. Smad proteins undergo multimerization with co-mediator Smad, Smad4, and translocated into the nucleus to regulate the transcription of target genes in cooperation with nuclear cofactors. The signal transduction pathway through activin type II receptors, ActRIIA and ActRIIB, with type I receptors is involved in various human diseases. In this review, we discuss the role of signaling through activin receptors as therapeutic targets of intractable neuromuscular diseases, endocrine disorders and cancers.
激活素、肌肉生长抑制素及转化生长因子-β（TGF-β）超家族的其他成员通过II型和I型受体的组合来传递信号，这两种受体均为跨膜丝氨酸/苏氨酸激酶。激活素II型受体ActRIIA和ActRIIB是激活素、节点蛋白、肌肉生长抑制素和生长分化因子11（GDF11）的主要配体结合受体。ActRIIs也能结合一部分骨形态发生蛋白（BMPs）。与ActRIIs形成复合物的I型受体依赖于配体。就激活素和节点蛋白而言，激活素受体样激酶4和7（ALK4和ALK7）是真正的I型受体。肌肉生长抑制素和GDF11利用ALK5，不过ALK4也可被这些生长因子激活。ALK4、5和7在结构和功能上相似，并激活TGF-β的受体调节型Smad蛋白Smad2和Smad3。BMPs通过三种II型受体BMPRII、ActRIIA和ActRIIB以及四种I型受体ALK1、2、3和6的组合来传递信号。BMPs激活BMP特异性的Smad蛋白Smad1、5和8。Smad蛋白与共介导因子Smad4发生多聚化，并转运至细胞核，与核辅因子协同调节靶基因的转录。通过激活素II型受体ActRIIA和ActRIIB与I型受体的信号转导通路涉及多种人类疾病。在本综述中，我们讨论了通过激活素受体传递信号作为难治性神经肌肉疾病、内分泌紊乱和癌症治疗靶点的作用。
