Dally regulates Dpp morphogen gradient formation by stabilizing Dpp on the cell surface
Dally regulates Dpp morphogen gradient formation by stabilizing Dpp on the cell surface
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DOI：
10.1016/j.ydbio.2007.10.035
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发表时间：
2008-01-01
影响因子：
2.7
通讯作者：
Nakato, Hiroshi
中科院分区：
文献类型：
--
作者：
Akiyama, Takuya;Kamimura, Keisuke;Nakato, Hiroshi
十肢麻痹蛋白（Decapentaplegic，Dpp）是果蝇骨形态发生蛋白的同源物，它作为形态发生原调节发育中翅膀前后轴沿着的模式化。以前的研究表明，Dally，硫酸乙酰肝素蛋白聚糖，调节Dpp形态原的分布和细胞对Dpp的反应。然而，Dally影响Dpp形态梯度的分子机制仍有待阐明。在这里，我们的特点是活动，稳定性和梯度形成的截断形式的DPP（DPP AN），它缺乏一个短的结构域在N-末端与达利的相互作用至关重要。Dpp（Delta N）在体外显示出与野生型Dpp相同的信号传导活性和蛋白质稳定性，但在体内具有较短的半衰期，这表明Dally稳定了细胞外基质中的Dpp。此外，遗传相互作用实验表明，达利拮抗厚脉（TPPs; Dpp I型受体）对Dpp信号传导的影响。考虑到Tglutamine可以通过受体介导的Dpp内吞作用下调Dpp信号传导，Dally拮抗Tglutamine的能力表明Dally抑制该过程。基于这些观察结果，我们提出了一个模型，其中Dally通过破坏受体介导的Dpp-受体复合物的内化和降解来调节Dpp的分布和信号传导。(c)2007年爱思唯尔公司All rights reserved.
Decapentaplegic (Dpp), a Drosophila homologue of bone morphogenetic proteins, acts as a morphogen to regulate patterning along the anterior-postenor axis of the developing wing. Previous studies showed that Dally, a heparan sulfate proteoglycan, regulates both the distribution of Dpp morphogen and cellular responses to Dpp. However, the molecular mechanism by which Dally affects the Dpp morphogen gradient remains to be elucidated. Here, we characterized activity, stability, and gradient formation of a truncated form of Dpp (Dpp AN), which lacks a short domain at the N-terminus essential for its interaction with Dally. Dpp(Delta N) shows the same signaling activity and protein stability as wild-type Dpp in vitro but has a shorter half-life in vivo, suggesting that Dally stabilizes Dpp in the extracellular matrix. Furthermore, genetic interaction experiments revealed that Dally antagonizes the effect of Thickveins (Tkv; a Dpp type I receptor) on Dpp signaling. Given that Tkv can downregulate Dpp signaling by receptor-mediated endocytosis of Dpp, the ability of dally to antagonize tkv suggests that Dally inhibits this process. Based on these observations, we propose a model in which Dally regulates Dpp distribution and signaling by disrupting receptor-mediated internalization and degradation of the Dpp-receptor complex. (c) 2007 Elsevier Inc. All rights reserved.