Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability
Nrarp functions to modulate neural-crest-cell differentiation by regulating LEF1 protein stability
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DOI：
10.1038/ncb1311
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发表时间：
2005-11-01
影响因子：
21.3
通讯作者：
Itoh, M
中科院分区：
文献类型：
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作者：
Ishitani, T;Matsumoto, K;Itoh, M
Nrarp （Notch-regulated锚蛋白重复序列蛋白）是一种具有两个锚蛋白重复序列的小蛋白（1-5）。尽管已知narp是Notch信号通路的抑制成分，在不同的发育过程中起作用（1,2,4,5），但narp在体内的作用尚未完全表征。在这里，我们发现narp是Wnt信号通路中的一个正调节因子。在斑马鱼中，通过反义morpholino oligonucletide （MO）敲低nrp -a的表达导致wnt信号依赖性神经嵴细胞发育的改变。nrp通过阻断LEF1泛素化来稳定Wnt信号级联中的关键转录因子LEF1蛋白。据此，在斑马鱼中，lef1基因的敲低表型与nrap -a基因的敲低表型相似，至少部分相似于其对多种组织发育的影响。此外，LEF1的激活并不影响Notch的活性，反之亦然。这些发现表明，nrap分别通过调节LEF1和Notch蛋白的转换来独立调节典型Wnt和Notch信号。
Nrarp (Notch-regulated ankyrin repeat protein) is a small protein that has two ankyrin repeats(1-5). Although Nrarp is known to be an inhibitory component of the Notch signalling pathway that operates in different developmental processes(1,2,4,5), the in vivo roles of Nrarp have not been fully characterized. Here, we show that Nrarp is a positive regulator in the Wnt signalling pathway. In zebrafish, knockdown of Nrarp-a expression by an antisense morpholino oligonucleotide (MO) results in altered Wnt-signalling-dependent neural-crest-cell development. Nrarp stabilizes LEF1 protein, a pivotal transcription factor in the Wnt signalling cascade, by blocking LEF1 ubiquitination. In accordance with this, the knockdown phenotype of lef1 is similar to that of nrarp-a, at least in part, in its effect on the development of multiple tissues in zebrafish. Furthermore, activation of LEF1 does not affect Notch activity or vice versa. These findings reveal that Nrarp independently regulates canonical Wnt and Notch signalling by modulating LEF1 and Notch protein turnover, respectively.