HEF1-Dependent aurora a activation induces disassembly of the primary cilium
HEF1-Dependent aurora a activation induces disassembly of the primary cilium
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DOI：
10.1016/j.cell.2007.04.035
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发表时间：
2007-06-29
期刊：
影响因子：
64.5
通讯作者：
Golemis, Erica A.
中科院分区：
文献类型：
--
作者：
Pugacheva, Elena N.;Jablonski, Sandra A.;Golemis, Erica A.
哺乳动物纤毛从极化细胞的顶端/腔表面突出，充当环境线索的传感器。许多发育障碍和病理状况已被证明是由纤毛相关信号蛋白的缺陷引起的。尽管越来越多的证据表明纤毛是协调细胞信号传导的重要场所，但人们对控制纤毛形成和分解的细胞机制知之甚少。在这里，我们发现前转移支架蛋白 HEF1/Cas-L/NEDD9 和纤毛基体的致癌极光 A (AurA) 激酶之间的相互作用导致 HDAC6（一种微管蛋白脱乙酰酶）磷酸化和激活，促进纤毛解体。我们表明，这条途径对于纤毛吸收来说既是必要的也是充分的，并且它构成了脊椎动物中 AurA 意想不到的非有丝分裂活性。此外，我们证明 AurA 和 HDAC6 的小分子抑制剂可以选择性地稳定纤毛，使其免受受调节吸收信号的影响，这表明这些临床药物有一种新的作用模式。
The mammalian cilium protrudes from the apical/lumenal surface of polarized cells and acts as a sensor of environmental cues. Numerous developmental disorders and pathological conditions have been shown to arise from defects in cilia-associated signaling proteins. Despite mounting evidence that cilia are essential sites for coordination of cell signaling, little is known about the cellular mechanisms controlling their formation and disassembly. Here, we show that interactions between the prometastatic scaffolding protein HEF1/Cas-L/NEDD9 and the oncogenic Aurora A (AurA) kinase at the basal body of cilia causes phosphorylation and activation of HDAC6, a tubulin deacetylase, promoting ciliary disassembly. We show that this pathway is both necessary and sufficient for ciliary resorption and that it constitutes an unexpected nonmitotic activity of AurA in vertebrates. Moreover, we demonstrate that small molecule inhibitors of AurA and HDAC6 selectively stabilize cilia from regulated resorption cues, suggesting a novel mode of action for these clinical agents.