Homeodomain-interacting protein kinases (Hipks) promote Wnt/Wg signaling through stabilization of β-catenin/Arm and stimulation of target gene expression
Homeodomain-interacting protein kinases (Hipks) promote Wnt/Wg signaling through stabilization of β-catenin/Arm and stimulation of target gene expression
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DOI：
10.1242/dev.025460
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发表时间：
2009-01-15
期刊：
影响因子：
4.6
通讯作者：
Verheyen, Esther M.
中科院分区：
文献类型：
--
作者：
Lee, Wendy;Swarup, Sharan;Verheyen, Esther M.
Wnt/Wingless（Wg）信号通路是一种保守的信号级联反应，参与多种生物学过程。Wnt/Wg信号转导的失调对发育具有深远的影响。同源结构域相互作用蛋白激酶（Hipks）代表丝氨酸/苏氨酸激酶的新家族。该组的成员（特别是Hipk 2）被认为是控制细胞生长、凋亡和发育的转录调节中的重要因子。在这里，我们提供的遗传和表型证据表明，唯一的果蝇这个家庭的成员，Hipk，作为一个积极的调节器在Wg途径的功能。hipk在翅膀中的表达挽救了Wg信号的丢失，而hipk的丢失可以增强降低的Wg信号表型。此外，hipk的缺失导致Arm蛋白水平降低，而hipk的过表达通过稳定Arm促进Wg信号，导致Wg应答靶标的激活。在Wg转录测定中，Hipk以激酶依赖的方式增强Tcf/Arm介导的基因表达。此外，Hipk可以结合臂和果蝇Tcf，和磷酸化臂。使用在体外和体内试验，Hipk被发现，以促进稳定的臂。我们观察到类似的分子之间的相互作用Lef 1/β-连环蛋白和脊椎动物Hipk 2，这表明Hipk蛋白在促进Wnt信号的直接和保守的作用。
The Wnt/Wingless (Wg) pathway represents a conserved signaling cascade involved in diverse biological processes. Misregulation of Wnt/Wg signal transduction has profound effects on development. Homeodomain-interacting protein kinases (Hipks) represent a novel family of serine/threonine kinases. Members of this group ( in particular Hipk2) are implicated as important factors in transcriptional regulation to control cell growth, apoptosis and development. Here, we provide genetic and phenotypic evidence that the sole Drosophila member of this family, Hipk, functions as a positive regulator in the Wg pathway. Expression of hipk in the wing rescues loss of the Wg signal, whereas loss of hipk can enhance decreased wg signaling phenotypes. Furthermore, loss of hipk leads to diminished Arm protein levels, whereas overexpression of hipk promotes the Wg signal by stabilizing Arm, resulting in activation of Wg responsive targets. In Wg transcriptional assays, Hipk enhanced Tcf/Arm-mediated gene expression in a kinase-dependent manner. In addition, Hipk can bind to Arm and Drosophila Tcf, and phosphorylate Arm. Using both in vitro and in vivo assays, Hipk was found to promote the stabilization of Arm. We observe similar molecular interactions between Lef1/beta-catenin and vertebrate Hipk2, suggesting a direct and conserved role for Hipk proteins in promoting Wnt signaling.