Regulation of TGFβ superfamily signaling by two separable domains of glypican LON-2 in C. elegans.
Regulation of TGFβ superfamily signaling by two separable domains of glypican LON-2 in C. elegans.
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DOI：
10.4161/worm.23843
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发表时间：
2013-07-01
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影响因子：
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通讯作者：
Gumienny TL
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作者：
Taneja-Bageshwar S;Gumienny TL
调节细胞间信号传导对于多细胞生物的正常发育和维持至关重要。磷脂酰肌醇蛋白聚糖已被证明在几种细胞环境中调节TGFβs、hedgehog和Wnt的信号传导。磷脂酰肌醇蛋白聚糖包括硫酸乙酰肝素、糖基磷脂酰肌醇（GPI）连接的细胞外蛋白的保守家族。Glypicans的结构复杂性可能是其功能复杂性的基础。在最近的一项研究中，我们建立在以前的发现基础上，两个C。线虫glypicans，LON-2，特异性抑制TGFβ超家族成员DBL-1的信号传导。我们测试了LON-2蛋白核心组分的功能要求和LON-2活性的翻译后修饰。我们提供了第一个证据表明磷脂酰肌醇蛋白聚糖的两个部分可以独立地调节体内TGFβ超家族信号传导：N-末端弗林蛋白酶产物和含有硫酸乙酰肝素附着位点的C-末端区域。此外，我们发现蛋白质-蛋白质相互作用基序对N-末端蛋白质核心中的LON-2活性至关重要，这表明LON-2通过充当DBL-1和RGD结合蛋白的支架而起作用。此外，我们通过显示C.线虫GPN-1不能在功能上替代LON-2。这项工作揭示了理解磷脂酰肌醇蛋白聚糖功能的复杂性和特异性的分子基础。
Regulated intercellular signaling is critical for the normal development and maintenance of multicellular organisms. Glypicans have been shown to regulate signaling by TGFβs, hedgehogs and Wnts, in several cellular contexts. Glypicans comprise a conserved family of heparan sulfated, glycosylphosphatidylinositol (GPI)-linked extracellular proteins. The structural complexity of glypicans may underlie their functional complexity. In a recent study31, we built on previous findings that one of the two C. elegans glypicans, LON-2, specifically inhibits signaling by the TGFβ superfamily member DBL-1. We tested the functional requirements of LON-2 protein core components and post-translational modifications for LON-2 activity. We provide the first evidence that two parts of a glypican can independently regulate TGFβ superfamily signaling in vivo: the N-terminal furin protease product and a C-terminal region containing heparan sulfate attachment sites. Furthermore, we show a protein-protein interaction motif is crucial for LON-2 activity in the N-terminal protein core, suggesting that LON-2 acts by serving as a scaffold for DBL-1 and an RGD-binding protein. In addition, we demonstrate specificity of glypican function by showing C. elegans GPN-1 does not functionally substitute for LON-2. This work reveals a molecular foundation for understanding the complexity and specificity of glypican function.