A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling.
A concentration-dependent endocytic trap and sink mechanism converts Bmper from an activator to an inhibitor of Bmp signaling.
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DOI：
10.1083/jcb.200808064
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发表时间：
2009-02-23
期刊：
影响因子：
--
通讯作者：
Patterson C
中科院分区：
文献类型：
--
作者：
Kelley R;Ren R;Pi X;Wu Y;Moreno I;Willis M;Moser M;Ross M;Podkowa M;Attisano L;Patterson C
Bmper与果蝇杂交种2同源，是一种以组织和阶段依赖的方式调节BMP活性的分泌因子。尽管Bmper影响BMP信号转导的分子机制尚不清楚，但Bmper的促BMP和抗BMP活性已被推测。在本文中，我们证明了当Bmper的摩尔浓度超过Bmp4时，Bmper会动态地从Bmp4信号的激活者转换为抑制者。通过一种新的内吞捕获和吸收机制抑制Bmp4，导致溶酶体有效地降解Bmper和Bmp4。Bmper介导的Bmp4内化减少了Bmp4依赖的Smad信号的持续时间和幅度。我们还确定，触发BMP内吞的是Noggin和Gremlin，而不是Chordin。这种细胞内转运途径扩大了选择性BMP调节剂的细胞外作用，包括细胞内调节。这种剂量依赖的分子开关解决了Bmper如何调节BMP活性的研究之间的不一致，并对分泌介质调节BMP信号具有广泛的意义。
Bmper, which is orthologous to Drosophila melanogaster crossveinless 2, is a secreted factor that regulates Bmp activity in a tissue- and stage-dependent manner. Both pro- and anti-Bmp activities have been postulated for Bmper, although the molecular mechanisms through which Bmper affects Bmp signaling are unclear. In this paper, we demonstrate that as molar concentrations of Bmper exceed Bmp4, Bmper dynamically switches from an activator to an inhibitor of Bmp4 signaling. Inhibition of Bmp4 through a novel endocytic trap-and-sink mechanism leads to the efficient degradation of Bmper and Bmp4 by the lysosome. Bmper-mediated internalization of Bmp4 reduces the duration and magnitude of Bmp4-dependent Smad signaling. We also determined that Noggin and Gremlin, but not Chordin, trigger endocytosis of Bmps. This endocytic transport pathway expands the extracellular roles of selective Bmp modulators to include intracellular regulation. This dosage-dependent molecular switch resolves discordances among studies that examine how Bmper regulates Bmp activity and has broad implications for Bmp signal regulation by secreted mediators.
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