Context-Dependent Activation or Inhibition of Wnt-β-Catenin Signaling by Kremen
Context-Dependent Activation or Inhibition of Wnt-β-Catenin Signaling by Kremen
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DOI：
10.1126/stke.18pe10
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发表时间：
2008-02-26
影响因子：
7.3
通讯作者：
Lee, Ethan
中科院分区：
文献类型：
--
作者：
Cselenyi, Christopher S.;Lee, Ethan
WNT-β-catenin信号控制后生动物发育的关键事件，其失调导致癌症和发育障碍。Wnt配体与其跨膜共受体FrizzledFZ和低密度脂蛋白受体相关蛋白(LRP5)或LRP6的结合可抑制转录共激活因子β-连环蛋白的降解，后者转位到细胞核以调节基因表达。分泌蛋白Dickkopf1(Dkk1)通过与LRP5和LRP6结合并阻断它们与Wnt和Fz的相互作用来抑制Wnt信号。Kreman 1和2(Krm1和Krm2，统称为Krms)是一种单通道跨膜Dkk1受体，通过促进LRP5和LRP6的内吞作用与Dkk1协同抑制Wnt信号。现在的一项研究表明，在缺乏Dkk1的情况下，Krms通过将LRP5和LRP6保持在质膜上来增强Wnt信号。有人认为，Dkk1的缺失或存在决定了Krms是激活还是抑制Wnt-β-catenin信号。在这里，我们推测Krms的上下文相关的积极和消极作用可能促进双相Wnt信号对Dkk1的浅梯度的响应，导致在发育过程中细胞之间产生精确而稳健的边界。识别Krms在Wnt-β-catenin信号转导中的上下文依赖角色有助于深入了解Wnt信号转导的机制，并具有重要的发育意义。
Wnt-beta-catenin signaling controls critical events in metazoan development, and its dysregulation leads to cancers and developmental disorders. Binding of a Wnt ligand to its transmembrane co-receptors Frizzled (Fz) and low-density lipoprotein (LDL) receptor-related protein (LRP) 5 or LRP6 inhibits the degradation of the transcriptional coactivator beta-catenin, which translocates to the nucleus to regulate gene expression. The secreted protein Dickkopf1 (Dkk1) inhibits Wnt signaling by binding to LRP5 and LRP6 and blocking their interaction with Wnt and Fz. Kremen 1 and 2 (Krm1 and 2, collectively termed Krms) are single-pass transmembrane Dkk1 receptors that synergize with Dkk1 to inhibit Wnt signaling by promoting the endocytosis of LRP5 and LRP6. A study now suggests that Krms, in the absence of Dkk1, potentiate Wnt signaling by maintaining LRP5 and LRP6 at the plasma membrane. It is proposed that the absence or presence of Dkk1 determines whether Krms will activate or inhibit Wnt-beta-catenin signaling, respectively. Here, we speculate that the proposed context-dependent positive and negative roles for Krms could promote biphasic Wnt signaling in response to a shallow gradient of Dkk1, resulting in the generation of precise and robust borders between cells during development. Identification of a context-dependent role for Krms in Wnt-beta-catenin signaling offers insight into the mechanism of Wnt signaling and has important developmental implications.