Department of Radiation Sciences, Oncology, Umeå University, 90187, Umeå, Sweden.
Oncology Research Laboratory, NUS M31, 90185, Umeå, Sweden.
Sci Rep. 2021 Apr 21;11(1):8585. doi: 10.1038/s41598-021-87949-7.
Netrin-1 is a secreted protein that is well known for its involvement in axonal guidance during embryonic development and as an enhancer of cancer cell metastasis. Despite extensive efforts, the molecular mechanisms behind many of the physiological functions of netrin-1 have remained elusive. Here, we show that netrin-1 functions as a suppressor of bone morphogenetic protein (BMP) signaling in various cellular systems, including a mutually inhibitory interaction with the BMP-promoting function of leucine-rich repeats and immunoglobulin-like domains (LRIG) proteins. The BMP inhibitory function of netrin-1 in mouse embryonic fibroblasts was dependent on the netrin receptor neogenin, with the expression level regulated by both netrin-1 and LRIG proteins. Our results reveal a previously unrecognized function of netrin-1 that may help to explain several of the developmental, physiological, and cancer-promoting functions of netrins at the signal transduction level.
轴突导向因子 Netrin-1 是一种分泌蛋白，在胚胎发育过程中对轴突导向具有重要作用，并且是促进癌细胞转移的增强子。尽管已经进行了广泛的研究，但 Netrin-1 的许多生理功能的分子机制仍然难以捉摸。在这里，我们表明 Netrin-1 在各种细胞系统中作为骨形态发生蛋白（BMP）信号的抑制剂发挥作用，包括与富含亮氨酸重复和免疫球蛋白样结构域（LRIG）蛋白的 BMP 促进功能的相互抑制作用。在小鼠胚胎成纤维细胞中，Netrin-1 的 BMP 抑制功能依赖于 Netrin 受体 Neogenin，其表达水平受 Netrin-1 和 LRIG 蛋白的共同调节。我们的结果揭示了 Netrin-1 的一个以前未被识别的功能，这可能有助于解释 Netrins 在信号转导水平上的几种发育、生理和促进癌症的功能。
