Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation.
Ulk4 promotes Shh signaling by regulating Stk36 ciliary localization and Gli2 phosphorylation.
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Ulk4通过调节Stk36纤毛定位和Gli2磷酸化促进Shh信号传导。
DOI：
10.7554/elife.88637
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发表时间：
2023-12-14
期刊：
影响因子：
7.7
通讯作者：
Jiang J
中科院分区：
文献类型：
--
作者：
Zhou M;Han Y;Jiang J
Hedgehog(HH)分泌蛋白家族通过转录因子Gli家族调控胚胎发育和成人组织动态平衡。Gli被认为是在初级纤毛顶端被激活的，但其潜在的机制仍然知之甚少。在这里，我们发现UNC-51样激酶4(UNC-51-like kinase4，ULK4)与ULK家族的另一个成员Stk36共同作用，促进Gli2磷酸化和HH途径的激活。Ulk4通过它的N-末端区域与Stk36相互作用，并通过它的调节域与Gli2相互作用，从而连接激酶和底物。虽然Ulk4对于HH诱导的Stk36激酶的激活是必不可少的，但对于Stk36纤毛尖端的定位、Gli2的磷酸化和激活是必不可少的。作为对HH的响应，Ulk4和Stk36都与纤毛尖端的Gli2共定位，并且Ulk4和Stk36的纤毛尖端积累相互依赖。我们进一步证明了Ulk4的纤毛定位依赖于Stk36的活性和Ulk4在Thr1023上的磷酸化，并且Ulk4的纤毛末端积累是其在HH途径中发挥功能所必需的。综上所述，我们的结果表明，Ulk4通过促进Stk36介导的纤毛尖端Gli2的磷酸化和激活来调节HH信号。
The Hedgehog (Hh) family of secreted proteins governs embryonic development and adult tissue homeostasis through the Gli family of transcription factors. Gli is thought to be activated at the tip of primary cilium, but the underlying mechanism has remained poorly understood. Here, we show that Unc-51-like kinase 4 (Ulk4), a pseudokinase and a member of the Ulk kinase family, acts in conjunction with another Ulk family member Stk36 to promote Gli2 phosphorylation and Hh pathway activation. Ulk4 interacts with Stk36 through its N-terminal region containing the pseudokinase domain and with Gli2 via its regulatory domain to bridge the kinase and substrate. Although dispensable for Hh-induced Stk36 kinase activation, Ulk4 is essential for Stk36 ciliary tip localization, Gli2 phosphorylation, and activation. In response to Hh, both Ulk4 and Stk36 colocalize with Gli2 at ciliary tip, and Ulk4 and Stk36 depend on each other for their ciliary tip accumulation. We further show that ciliary localization of Ulk4 depends on Stk36 kinase activity and phosphorylation of Ulk4 on Thr1023, and that ciliary tip accumulation of Ulk4 is essential for its function in the Hh pathway. Taken together, our results suggest that Ulk4 regulates Hh signaling by promoting Stk36-mediated Gli2 phosphorylation and activation at ciliary tip.
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影响因子：
4.4
作者：
Zhou, Mengmeng;Han, Yuhong;Wang, Bing;Cho, Yong Suk;Jiang, Jin
通讯作者：
Jiang, Jin
通过 Fused 的二聚化和 Cubitus Interruptus 的核转位来转导 Hedgehog 信号
影响因子：
44.1
作者：
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刺猬通过磷酸化激活融合，以引起各种途径响应。
影响因子：
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作者：
Zhou, Qianhe;Kalderon, Daniel
通讯作者：
Kalderon, Daniel
影响因子：
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作者：
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通讯作者：
Ding YQ
影响因子：
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作者：
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通讯作者：
Jiang J