Dishevelled-3 C-terminal His single amino acid repeats are obligate for Wnt5a activation of non-canonical signaling.
Dishevelled-3 C-terminal His single amino acid repeats are obligate for Wnt5a activation of non-canonical signaling.
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DOI：
10.1186/1750-2187-5-19
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发表时间：
2010-11-23
影响因子：
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通讯作者：
Wang HY
中科院分区：
文献类型：
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作者：
Ma L;Wang Y;Malbon CC;Wang HY
Wnt非经典途径(Wnt5a&Gt；Frizzled2&Gt；环状GMP磷酸二酯酶/钙动员途径调节核因子-AT的激活)由三个哺乳动物Dvl1、Dvl2和Dvl3介导，并询问了Dvl3特有的C末端区域的作用。Dvl1、Dvl2和Dvl3在小鼠全能F9胚胎畸胎癌细胞中有不同程度的表达。通过siRNA下调每个内源性DVL亚型的表达，是Wnt5a激活NF-AT敏感转录的必备条件。效应器上游的元件，如cGMP磷酸二酯酶和钙动员，被任何一个Dvl击倒而被阻断；因此，对于Wnt5a，NF-AT Dvl的激活不是多余的。在DVL的三种异构体中，Dvl3的C端序列差异最大。Dvl3区域的缺失取消了Wnt5a刺激的信号转导。组氨酸(His)的丙氨酸(Ala)取代Dvl3中637,638和/或647,648处的单一氨基酸重复，与C端缺失一样，取消了Wnt 5a信号的传播。Dvl3中相同的His重复序列的苯丙氨酸(Phe)替代模拟了Wnt5a刺激的NF-AT敏感转录。Dvl3的C端1/3及其单一氨基酸重复序列637、638和647,648是Dv13所特有并保守的，是Wnt5a激活非正则途径所必需的，而不是Wnt3a激活正则途径所必需的。
The Wnt non-canonical pathway (Wnt5a > Frizzled-2 > cyclic GMP phosphodiesterase/Ca2+-mobilization pathway regulates the activation of NF-AT) is mediated by three mammalian Dishevelleds (Dvl1, Dvl2, and Dvl3) and the role of the C-terminal region unique to Dvl3 was interrogated. Dvl1, Dvl2, and Dvl3 are expressed at varying levels in mouse totipotent F9 embryonal teratocarcinoma cells. The expression of each endogenous Dvl isoform, as defined by knock-down with siRNA, was obligate for Wnt5a to activate NF-AT-sensitive transcription. Elements upstream of effectors, e.g., cGMP phosphodiesterase and Ca2+-mobilization, were blocked by knock-down of any one of the Dvls; thus, with respect to Wnt5a activation of NF-AT Dvls are not redundant. Among the three Dvl isoforms, the C-terminal sequence of Dvl3 is the most divergent. Deletion of region of Dvl3 abolishes Wnt5a-stimulated signaling. Alanine (Ala)-substitution of histidine (His) single amino acid repeats at 637,638 and/or 647,648 in Dvl3, like C-terminal deletion, abolishes Wnt 5a signal propagation. Phenylalanine (Phe)-substitution of the same His-repeats in Dvl3 mimics Wnt5a stimulated NF-AT-sensitive transcription. The C-terminal third of Dvl3 and His single amino acid repeats 637,638 and 647,648 (which are unique to and conserved in Dvl3) are essential for Wnt5a activation of the non-canonical pathway, but not the Wnt3a activation of the canonical pathway.