Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans
Novel Contact-dependent Bone Morphogenetic Protein (BMP) Signaling Mediated by Heparan Sulfate Proteoglycans
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DOI：
10.1074/jbc.m110.208082
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发表时间：
2011-05-13
影响因子：
4.8
通讯作者：
Nakato, Hiroshi
中科院分区：
文献类型：
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作者：
Dejima, Katsufumi;Kanai, Makoto I.;Nakato, Hiroshi
我们以前提出了一个模型，DALLY，果蝇磷脂酰肌醇蛋白聚糖，作为一个反式共受体调节BMP信号在生殖系干细胞龛。为了研究接触依赖性BMP信号传导的分子机制，我们开发了新的体外检测系统来监测果蝇S2细胞的反式信号传导。使用基于免疫印迹以及单细胞测定系统，我们提出的证据表明，果蝇glypicans确实增强BMP信号在反式接触依赖性的方式在体外。我们的分析表明，硫酸乙酰肝素修饰是DALLY的反式共受体活性所必需的。在S2细胞中，两种BMP样分子，Decapentaplegic（DPP）和Glass bottom boat，可以通过硫酸乙酰肝素蛋白聚糖共受体介导反式信号传导。体外系统反映了先前在体内观察到的硫酸乙酰肝素蛋白聚糖功能的分子特征，例如配体特异性和依赖于配体剂量的双相活性。此外，使用DALLY包被表面的实验表明，DALLY通过其对接触细胞表面上DPP蛋白的稳定性的影响来反式调节DPP信号传导。我们的研究结果为新型接触依赖性信号传导提供了分子基础，该信号传导定义了体内干细胞生态位的物理空间。
We previously proposed a model that DALLY, a Drosophila glypican, acts as a trans co-receptor to regulate BMP signaling in the germ line stem cell niche. To investigate the molecular mechanisms of contact-dependent BMP signaling, we developed novel in vitro assay systems to monitor trans signaling using Drosophila S2 cells. Using immunoblot-based as well as single-cell assay systems, we present evidence that Drosophila glypicans indeed enhance BMP signaling in trans in a contact-dependent manner in vitro. Our analysis showed that heparan sulfate modification is required for the trans co-receptor activity of DALLY. Two BMP-like molecules, Decapentaplegic (DPP) and Glass bottom boat, can mediate trans signaling through a heparan sulfate proteoglycan co-receptor in S2 cells. The in vitro systems reflect the molecular characteristics of heparan sulfate proteoglycan functions observed previously in vivo, such as ligand specificity and biphasic activity dependent on the ligand dosage. In addition, experiments using a DALLY-coated surface suggested that DALLY regulates DPP signaling in trans by its effect on the stability of DPP protein on the surface of the contacting cells. Our findings provide the molecular foundation for novel contact-dependent signaling, which defines the physical space of the stem cell niche in vivo.