Regulation of Autophosphorylation Controls PLK4 Self-Destruction and Centriole Number
Regulation of Autophosphorylation Controls PLK4 Self-Destruction and Centriole Number
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DOI：
10.1016/j.cub.2013.09.037
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发表时间：
2013-11-18
期刊：
影响因子：
9.2
通讯作者：
Bettencourt-Dias, Monica
中科院分区：
文献类型：
--
作者：
Cunha-Ferreira, Ines;Bento, Ines;Bettencourt-Dias, Monica
Polo样激酶4（PLK 4）是中心粒生物发生的主要参与者：如果没有它，中心粒就无法形成，而过量则会导致中心粒扩增[1-5]。SCF-Slimb/β TrCP-E3泛素连接酶通过识别保守的磷酸降解决定子来控制PLK 4水平[6-13]。SCF-Slimb/β TrCP底物结合和靶向降解通常由磷酸化级联调节，控制复杂过程，如生物钟和形态发生[14]。在这里，我们表明PLK 4是一种自杀激酶，在SCF-Slimb/β TrCP结合的关键残基中自磷酸化。我们证明了一个多位点反式自磷酸化机制，可能确保PLK 4浓度达到阈值，并在PLK 4可以自毁之前观察到一系列事件。首先，我们表明PLK 4在降解决定子内的Ser 293和Thr 297上反式自磷酸化其他PLK 4分子，并且这些残基对PLK 4降解的贡献不同，第一个是关键的，第二个是最大化的自破坏。其次，PLK 4反式自磷酸化降解决定子外的磷酸簇，其调节Thr 297磷酸化、PLK 4降解和中心粒数目。最后，我们显示PLK 4-Slimb/β TrCP调节的重要性，因为它在索马和生殖细胞中运作。由于β TrCP、PLK 4和中心粒数量在几种癌症中失调[14-17]，我们的工作提供了中心粒数量控制和肿瘤发生之间的新联系。
Polo-like kinase 4 (PLK4) is a major player in centriole biogenesis: in its absence centrioles fail to form, while in excess leads to centriole amplification [1-5]. The SCF-Slimb/beta TrCP-E3 ubiquitin ligase controls PLK4 levels through recognition of a conserved phosphodegron [6-13]. SCF-Slimb/beta TrCP substrate binding and targeting for degradation is normally regulated by phosphorylation cascades, controlling complex processes, such as circadian clocks and morphogenesis [14]. Here, we show that PLK4 is a suicide kinase, autophosphorylating in residues that are critical for SCF-Slimb/beta TrCP binding. We demonstrate a multisite trans-autophosphorylation mechanism, likely to ensure that both a threshold of PLK4 concentration is attained and a sequence of events is observed before PLK4 can autodestruct. First, we show that PLK4 trans-autophosphorylates other PLK4 molecules on both Ser293 and Thr297 within the degron and that these residues contribute differently for PLK4 degradation, the first being critical and the second maximizing auto-destruction. Second, PLK4 trans-autophosphorylates a phospho-cluster outside the degron, which regulates Thr297 phosphorylation, PLK4 degradation, and centriole number. Finally, we show the importance of PLK4-Slimb/beta TrCP regulation as it operates in both soma and germline. As beta TrCP, PLK4, and centriole number are deregulated in several cancers [14-17], our work provides novel links between centriole number control and tumorigenesis.