Dual Function of UNC-51-like Kinase 3 (Ulk3) in the Sonic Hedgehog Signaling Pathway
Dual Function of UNC-51-like Kinase 3 (Ulk3) in the Sonic Hedgehog Signaling Pathway
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DOI：
10.1074/jbc.m110.133991
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发表时间：
2010-09-24
影响因子：
4.8
通讯作者：
Kogerman, Priit
中科院分区：
文献类型：
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作者：
Maloverjan, Alla;Piirsoo, Marko;Kogerman, Priit
Sonic hedgehog （Shh）信号通路控制多种发育过程，并与成人组织稳态维持和神经发生有关。最近，我们发现Ulk3是一种活性激酶，能够正向调节哺乳动物Shh信号的介质Gli蛋白。在这里，我们提供了几条线的证据，表明Ulk3参与Shh信号的转导，也独立于其激酶活性。我们证明Ulk3通过其激酶结构域与融合抑制因子（Sufu）相互作用，融合抑制因子是Gli蛋白负调控所需的蛋白质。素复阻断Ulk3的自磷酸化，并使其丧失磷酸化和正向调节Gli蛋白的能力。我们发现Shh信号会破坏Sufu-Ulk3复合物的稳定并诱导Ulk3的释放。我们证明Sufu-Ulk3复合物与Gli2共表达时，促进了Gli2抑制因子形式的产生，并且在sh应答细胞中Ulk3 mRNA水平的降低导致细胞更有效地传递Shh信号。我们的数据表明Ulk3在Shh信号转导通路中具有双重功能，并提出了Sufu通过结合和抑制Ulk3调节Gli蛋白的另一种方式。
The Sonic hedgehog (Shh) signaling pathway controls a variety of developmental processes and is implicated in tissue homeostasis maintenance and neurogenesis in adults. Recently, we identified Ulk3 as an active kinase able to positively regulate Gli proteins, mediators of the Shh signaling in mammals. Here, we provide several lines of evidence that Ulk3 participates in the transduction of the Shh signal also independently of its kinase activity. We demonstrate that Ulk3 through its kinase domain interacts with Suppressor of Fused (Sufu), a protein required for negative regulation of Gli proteins. Sufu blocks Ulk3 autophosphorylation and abolishes its ability to phosphorylate and positively regulate Gli proteins. We show that Shh signaling destabilizes the Sufu-Ulk3 complex and induces the release of Ulk3. We demonstrate that the Sufu-Ulk3 complex, when co-expressed with Gli2, promotes generation of the Gli2 repressor form, and that reduction of the Ulk3 mRNA level in Shh-responsive cells results in higher potency of the cells to transmit the Shh signal. Our data suggests a dual function of Ulk3 in the Shh signal transduction pathway and propose an additional way of regulating Gli proteins by Sufu, through binding to and suppression of Ulk3.