Levine Ariel J, Levine Zachary J, Brivanlou Ali H
Laboratory of Molecular Vertebrate Embryology, The Rockefeller University, New York, NY, USA.
Dev Biol. 2009 Jan 1;325(1):43-8. doi: 10.1016/j.ydbio.2008.09.006. Epub 2008 Sep 18.
Within the TGF-beta superfamily, there are approximately forty ligands divided into two major branches: the TGF-beta/Activin/Nodal ligands and the BMP/GDF ligands. We studied the ligand GDF3 and found that it inhibits signaling by its co-family members, the BMPs; however, GDF3 has been described by others to have Nodal-like activity. Here, we show that GDF3 can activate Nodal signaling, but only at very high doses and only upon mRNA over-expression. In contrast, GDF3 inhibits BMP signaling upon over-expression of GDF3 mRNA, as recombinant protein, and regardless of its dose. We therefore further characterized the mechanism through which GDF3 protein acts as a specific BMP inhibitor and found that the BMP inhibitory activity of GDF3 resides redundantly in the unprocessed, predominant form and in the mature form of the protein. These results confirm and extend the activity that we described for GDF3 and illuminate the experimental basis for the different observations of others. We suggest that GDF3 is either a bi-functional TGF-beta ligand, or, more likely, that it is a BMP inhibitor that can artificially activate Nodal signaling under non-physiological conditions.
在转化生长因子-β（TGF-β）超家族中，大约有40种配体，分为两个主要分支：TGF-β/激活素/节点配体和骨形态发生蛋白（BMP）/生长分化因子（GDF）配体。我们研究了配体GDF3，发现它抑制其同家族成员BMP的信号传导；然而，其他人已描述GDF3具有类似节点的活性。在此，我们表明GDF3可以激活节点信号传导，但仅在非常高的剂量下且仅在mRNA过表达时才会激活。相比之下，无论剂量如何，当GDF3 mRNA作为重组蛋白过表达时，GDF3都会抑制BMP信号传导。因此，我们进一步表征了GDF3蛋白作为特异性BMP抑制剂发挥作用的机制，发现GDF3的BMP抑制活性冗余地存在于未加工的、占主导地位的形式以及该蛋白的成熟形式中。这些结果证实并扩展了我们所描述的GDF3的活性，并阐明了其他人不同观察结果的实验基础。我们认为，GDF3要么是一种双功能TGF-β配体，要么更有可能是一种BMP抑制剂，它可以在非生理条件下人工激活节点信号传导。
