Heparan sulfate acts as a bone morphogenetic protein coreceptor by facilitating ligand-induced receptor hetero-oligomerization.
Heparan sulfate acts as a bone morphogenetic protein coreceptor by facilitating ligand-induced receptor hetero-oligomerization.
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DOI：
10.1091/mbc.e10-04-0348
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发表时间：
2010-11-15
影响因子：
3.3
通讯作者：
Lander AD
中科院分区：
文献类型：
--
作者：
Kuo WJ;Digman MA;Lander AD
细胞表面硫酸乙酰肝素(HS)可增强多种生长因子的活性。在这里，我们发现HS通过促进II型受体亚单位募集到BMP-I型受体复合体来刺激BMP的活性，这表明HS是形成信号复合体的催化剂。细胞表面的硫酸乙酰肝素(HS)不仅能结合几种主要的生长因子，有时还能增强它们的活性--这种效应通常被称为“共受体”。一种观点认为共接受是由于生长因子-受体相互作用的稳定，这一观点主要来自于对成纤维细胞生长因子(FGFs)的研究。最近的体内研究强烈表明，HS在骨形态发生蛋白(BMPs)的信号调节中也发挥着重要作用。在这里，我们提供的证据表明，BMP的共接受机制与FGFs所建立的机制明显不同。首先，我们展示了细胞表面HS在BMP2和BMP4的即时信号活动中的直接刺激作用，我们提供了证据表明HS-BMP相互作用是这种作用所必需的。接下来，使用几种独立的配体结合和受体组装的分析，包括免疫共沉淀、交联和荧光波动显微镜，我们表明HS不影响BMP与I型受体亚单位的结合，而是促进了II型受体亚单位随后向BMP-I型受体复合体的募集。这表明HS是信号复合体形成的催化剂，而不是生长因子结合的稳定剂。
Cell surface heparan sulfate (HS) potentiates the activities of various growth factors. Here we show that HS stimulates bone morphogenetic protein (BMP) activity by enhancing recruitment of type II receptor subunits to BMP-type I receptor complexes, suggesting a view of HS as a catalyst of the formation of signaling complexes. Cell surface heparan sulfate (HS) not only binds several major classes of growth factors but also sometimes potentiates their activities—an effect usually termed “coreception.” A view that coreception is due to the stabilization of growth factor–receptor interactions has emerged primarily from studies of the fibroblast growth factors (FGFs). Recent in vivo studies have strongly suggested that HS also plays an important role in regulating signaling by the bone morphogenetic proteins (BMPs). Here, we provide evidence that the mechanism of coreception for BMPs is markedly different from that established for FGFs. First, we demonstrate a direct, stimulatory role for cell surface HS in the immediate signaling activities of BMP2 and BMP4, and we provide evidence that HS–BMP interactions are required for this effect. Next, using several independent assays of ligand binding and receptor assembly, including coimmunoprecipitation, cross-linking, and fluorescence fluctuation microscopy, we show that HS does not affect BMP binding to type I receptor subunits but instead enhances the subsequent recruitment of type II receptor subunits to BMP-type I receptor complexes. This suggests a view of HS as a catalyst of the formation of signaling complexes, rather than as a stabilizer of growth factor binding.