A tale of two receptors: Bmp heterodimers recruit two type I receptors but use the kinase activity of only one.
A tale of two receptors: Bmp heterodimers recruit two type I receptors but use the kinase activity of only one.
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两种受体的故事：Bmp 异二聚体招募两种 I 型受体，但仅使用其中一种的激酶活性。
DOI：
10.1073/pnas.2104745118
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发表时间：
2021
影响因子：
11.1
通讯作者：
Christian,Jan
中科院分区：
文献类型：
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作者：
Christian,Jan
骨形态发生蛋白(BMP)是较大的转化生长因子β(β)家族的成员，在胚胎发育、成人组织动态平衡和人类疾病中发挥不同的作用(1)。BMP根据序列相似性被分成亚家族，它们可以作为同源二聚体或异源二聚体发出信号。众所周知，BMP2和BMP4组成一个亚家族，可以与属于不同亚家族的BMP5、BMP6或BMP7异源二聚，并且这些异二聚体的每分子活性显著高于它们各自的同源二聚体(2)。例如，BMP2、BMP4、BMP5、BMP6或BMP7的同源二聚体都可以诱导骨形成，但BMP2/5、BMP2/6、BMP2/7和BMP4/7的异源二聚体在较低浓度(3-5)时可以诱导骨形成。同样，BMP2/6异二聚体在胚胎干细胞中激活下游信号的能力增强(6)，BMP2/7和Bmp4/7异二聚体在非洲爪哇和斑马鱼中表现出诱导腹侧命运的能力增强(7，8)。最近的研究表明，内源性BMP2/7、BMP4/7或BMP2/6异源二聚体在许多体内环境中是专有的信号配体，包括果蝇(9)和斑马鱼胚胎(10)的背腹模式，早期小鼠胚胎的细胞命运规范和模式(11)，以及成年小鼠铁稳态的调节(12)。尽管越来越多的证据表明BMP异二聚体需要在体内发出信号，但为什么这些异二聚体比同二聚体具有更高的每分子活性仍然是一个谜。在PNAS中，Tajer等人(13)通过探索BMP拮抗剂和受体在增强BMP异二聚体效力方面的潜在作用，揭示了这个长期存在的难题。
Bone morphogenetic proteins (BMPs) are members of the larger transforming growth factor β (TGF-β) family of cytokines that play diverse roles in embryonic development, adult tissue homeostasis, and human disease (1). BMPs are grouped into subfamilies based on sequence similarity, and can signal as either homodimers or heterodimers. It has been known for over 25 y that BMP2 and BMP4, which comprise one subfamily, can heterodimerize with BMP5, BMP6, or BMP7, which belong to a distinct subfamily, and that these heterodimeric ligands have significantly higher per-molecule activity than their respective homodimers (2). For example, homodimers of BMP2, BMP4, BMP5, BMP6, or BMP7 can all induce bone formation, but BMP2/5, BMP2/6, BMP2/7, and BMP4/7 heterodimers can do so at 30-to 50-fold lower concentrations (3–5). Likewise, BMP2/6 heterodimers show enhanced ability to activate downstream signaling in embryonic stem cells (6), and Bmp2/7 and Bmp4/7 heterodimers show heightened ability to induce ventral fate in Xenopus and zebrafish (7, 8). More-recent studies have shown that endogenous BMP2/7, BMP4/7, or BMP2/6 heterodimers are the obligate signaling ligands in a number of in vivo contexts, including during dorsoventral patterning in Drosophila (9) and zebrafish embryos (10), cell fate specification and patterning in early mouse embryos (11), and regulation of iron homeostasis in adult mice (12). Despite growing evidence that BMP heterodimers are required to signal in vivo, the reasons why these heterodimers have higher per-molecule activity than homodimers has remained a mystery. In PNAS, Tajer et al.(13) cast light on this longstanding conundrum by exploring potential roles for BMP antagonists and receptors in enhancing the potency of BMP heterodimers.