Kim Sehyun, Lee Kwanwoo, Choi Jung-Hwan, Ringstad Niels, Dynlacht Brian David
Department of Pathology, New York University Cancer Institute, New York University School of Medicine, New York, New York 10016, USA.
Skirball Institute of Biomolecular Medicine, Molecular Neurobiology Program, New York University School of Medicine, New York, New York 10016, USA.
Nat Commun. 2015 Aug 20;6:8087. doi: 10.1038/ncomms9087.
Many proteins are known to promote ciliogenesis, but mechanisms that promote primary cilia disassembly before mitosis are largely unknown. Here we identify a mechanism that favours cilium disassembly and maintains the disassembled state. We show that co-localization of the S/G2 phase kinase, Nek2 and Kif24 triggers Kif24 phosphorylation, inhibiting cilia formation. We show that Kif24, a microtubule depolymerizing kinesin, is phosphorylated by Nek2, which stimulates its activity and prevents the outgrowth of cilia in proliferating cells, independent of Aurora A and HDAC6. Our data also suggest that cilium assembly and disassembly are in dynamic equilibrium, but Nek2 and Kif24 can shift the balance toward disassembly. Further, Nek2 and Kif24 are overexpressed in breast cancer cells, and ablation of these proteins restores ciliation in these cells, thereby reducing proliferation. Thus, Kif24 is a physiological substrate of Nek2, which regulates cilia disassembly through a concerted mechanism involving Kif24-mediated microtubule depolymerization.
已知许多蛋白质可促进纤毛生成,但在有丝分裂前促进初级纤毛解聚的机制在很大程度上尚不清楚。在此,我们确定了一种有利于纤毛解聚并维持解聚状态的机制。我们发现,S/G2期激酶Nek2和Kif24的共定位会触发Kif24磷酸化,从而抑制纤毛形成。我们表明,Kif24是一种使微管解聚的驱动蛋白,被Nek2磷酸化,这会刺激其活性并阻止增殖细胞中纤毛的生长,且不依赖于极光激酶A和组蛋白去乙酰化酶6。我们的数据还表明,纤毛组装和解聚处于动态平衡,但Nek2和Kif24可使平衡向解聚方向转变。此外,Nek2和Kif24在乳腺癌细胞中过表达,去除这些蛋白质可恢复这些细胞中的纤毛形成,从而减少增殖。因此,Kif24是Nek2的生理底物,Nek2通过一种涉及Kif24介导的微管解聚的协同机制来调节纤毛解聚。