Role of the intracellular domains of LRP5 and LRP6 in activating the Wnt canonical pathway
Role of the intracellular domains of LRP5 and LRP6 in activating the Wnt canonical pathway
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DOI：
10.1002/jcb.20400
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发表时间：
2005-05-15
影响因子：
4
通讯作者：
Johnson, GVW
中科院分区：
文献类型：
--
作者：
Mi, KH;Johnson, GVW
LDL受体相关蛋白5和6（LRP 5/6）是Frizzled受体的共受体，其介导Wnt诱导的转录因子家族TCF/LEF-1的活化。尽管LRP 5和LRP 6是高度同源的，但LRP 6而不是LRP 5主要在神经系统中表达，并且LRP 6基因的缺失导致显著的脑异常，而LRP 5的缺失主要导致骨密度降低。此外，LRP 5和LRP 6的确切功能尚未明确定义，尽管很明显它们都在Wnt经典途径中发挥关键作用。在这项研究中，LRP 5/6的细胞内结构域在介导Wnt信号传导中的作用进行了检查。在不存在外源Wnt 3a的情况下，全长（FL）LRP 6而非LRP 5增加TCF/LEF-1转录活性，然而两者均显著增强Wnt 3a诱导的TCF/LEF-1活化。与FL构建体的发现相反，LRP 5和LRP 6的细胞内结构域（膜锚定和胞质）在不存在Wnt 3a的情况下显著增加TCF/LEF-1活化，并增强Wnt 3a诱导的β-连环蛋白磷酸化的降低、游离β-连环蛋白水平的增加和TCF/LEF-1活性的增加。这些发现表明：（1）LRP 5和LRP 6在Wnt 3a不存在的情况下差异性地调节TCF/LEF-1活化，和（2）LRP 5/6的细胞内C末端结构域增强Wnt 3a诱导的TCF/LEF-1活化，无论它们是否是膜锚定的。这些发现为LRP 5/6在调节经典Wnt信号传导中的作用提供了重要的新见解。(c)2005 Wiley-Liss，Inc.
LDL-receptor related proteins 5 and 6 (LRP5/6) are co-receptors of Frizzled receptors that mediate Wnt-induced activation of the transcription factor family TCF/LEF-1. Even though LRP5 and LRP6 are highly homologous, LRP6, but not LRP5, is expressed primarily in the nervous system and deletion of the LRP6 gene results in significant brain abnormalities, while deletion of LRP5 results in primarily decreased bone density. Additionally, the exact function of LRP5 and LRP6 have not been clearly defined, although it is clear that they both play key roles in the Wnt canonical pathway. In this study the role of the intracellular domains of LRP5/6 in mediating Wnt signaling was examined. In the absence of exogenous Wnt 3a, full-length (FL) LRP6, but not LRP5, increased TCF/LEF-1 transcriptional activity, however both significantly potentiated Wnt 3a-induced TCF/LEF-1 activation. In contrast to the findings with the FL constructs, the intracellular domains (membrane-anchored and cytosolic) of both LRP5 and LRP6 significantly increased TCF/LEF-1 activation in the absence of Wnt 3a, and potentiated the Wnt 3a-induced decrease in beta-catenin phosphorylation, increase in free beta-catenin levels and the increase in TCF/LEF-1 activity. These findings demonstrate that: (1) LRP5 and LRP6 differentially modulate TCF/LEF-1 activation in the absence of Wnt 3a and (2) the intracellular C-terminal domains of LRP5/6 potentiate Wnt 3a-induced TCF/LEF-1 activation whether or not they are membrane-anchored. These findings provide significant new insights into the roles of LRP5/6 in modulating canonical Wnt signaling. (c) 2005 Wiley-Liss, Inc.