Latent TGF-β-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly
Latent TGF-β-binding protein 2 binds to DANCE/fibulin-5 and regulates elastic fiber assembly
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DOI：
10.1038/sj.emboj.7601768
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发表时间：
2007-07-25
期刊：
影响因子：
11.4
通讯作者：
Nakamura, Tomoyuki
中科院分区：
文献类型：
--
作者：
Hirai, Maretoshi;Horiguchi, Masahito;Nakamura, Tomoyuki
弹性纤维在为人体各种器官（如动脉、肺和皮肤）提供弹性和完整性方面发挥着主要作用。然而，导致弹性蛋白沿微纤维沉积和交联的弹性纤维组装的分子机制在很大程度上仍然未知。我们之前已经通过研究DANCE缺陷小鼠表明，发育中的动脉和神经嵴egf样蛋白（DANCE）（也称为纤维蛋白-5）对于弹性形成至关重要。在这里，我们报告了潜在转化生长因子- β结合蛋白2 （LTBP-2）作为dance结合蛋白的鉴定，这是一种弹性纤维相关蛋白，其在弹性发生中的功能尚不清楚。利用人皮肤成纤维细胞进行的弹性生成实验显示，DANCE和弹性蛋白的纤维沉积在很大程度上依赖于纤维蛋白-1微原纤维。然而，LTBP-2的下调诱导了DANCE和弹性蛋白不依赖于纤维蛋白1的纤维沉积。此外，重组LTBP-2促进DANCE在纤原蛋白-1微纤维上的沉积。这些结果提示了一种新的弹性纤维组装调节机制，其中LTBP-2调节DANCE靶向合适的微纤维以形成弹性纤维。
Elastic fibers play the principal roles in providing elasticity and integrity to various types of human organs, such as the arteries, lung, and skin. However, the molecular mechanism of elastic fiber assembly that leads to deposition and crosslinking of elastin along microfibrils remains largely unknown. We have previously shown that developing arteries and neural crest EGF-like protein (DANCE) ( also designated fibulin-5) is essential for elastogenesis by studying DANCE-deficient mice. Here, we report the identification of latent transforming growth factor-beta-binding protein 2 (LTBP-2), an elastic fiber-associating protein whose function in elastogenesis is not clear, as a DANCE-binding protein. Elastogenesis assays using human skin fibroblasts reveal that fibrillar deposition of DANCE and elastin is largely dependent on fibrillin-1 microfibrils. However, downregulation of LTBP-2 induces fibrillin-1-independent fibrillar deposition of DANCE and elastin. Moreover, recombinant LTBP-2 promotes deposition of DANCE onto fibrillin-1 microfibrils. These results suggest a novel regulatory mechanism of elastic fiber assembly in which LTBP-2 regulates targeting of DANCE on suitable microfibrils to form elastic fibers.