Plk4 trans-autophosphorylation regulates centriole number by controlling βTrCP-mediated degradation
Plk4 trans-autophosphorylation regulates centriole number by controlling βTrCP-mediated degradation
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DOI：
10.1242/jcs.068502
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发表时间：
2010-07-01
影响因子：
4
通讯作者：
Nigg, Erich A.
中科院分区：
文献类型：
--
作者：
Guderian, Gernot;Westendorf, Jens;Nigg, Erich A.
中心粒是哺乳动物中心体的主要组成部分，是纤毛发生的基体。中心体在分裂间期组织细胞质微管网络，在有丝分裂期间组织有丝分裂纺锤体，并且中心体数目的异常与染色体不稳定和肿瘤形成有关。中心粒蛋白Polo样激酶4（Plk 4）是中心粒生物发生的关键调节因子，对于维持恒定的中心粒数量至关重要，但调节其活性和表达的机制才刚刚开始出现。在这里，我们表明，人类Plk 4是受β TrCP依赖性蛋白酶体降解，这表明这条途径是保守的从果蝇到人类。出乎意料的是，我们发现激酶死亡的Plk 4的稳定过表达导致中心粒过度复制。这种表型取决于内源性野生型Plk 4的存在。我们的数据表明，中心粒过度复制的结果从破坏的激酶死亡的Plk 4，然后屏蔽内源性Plk 4识别β TrCP的Plk 4的反式自磷酸化。我们的结论是，活性Plk 4促进其自身的降解，催化β TrCP结合通过trans-autophosphorylation（磷酸化的其他激酶的二聚体）内同源二聚体。
Centrioles are the main constituents of the mammalian centrosome and act as basal bodies for ciliogenesis. Centrosomes organize the cytoplasmic microtubule network during interphase and the mitotic spindle during mitosis, and aberrations in centrosome number have been implicated in chromosomal instability and tumor formation. The centriolar protein Polo-like kinase 4 (Plk4) is a key regulator of centriole biogenesis and is crucial for maintaining constant centriole number, but the mechanisms regulating its activity and expression are only beginning to emerge. Here, we show that human Plk4 is subject to beta TrCP-dependent proteasomal degradation, indicating that this pathway is conserved from Drosophila to human. Unexpectedly, we found that stable overexpression of kinase-dead Plk4 leads to centriole overduplication. This phenotype depends on the presence of endogenous wild-type Plk4. Our data indicate that centriole overduplication results from disruption of Plk4 trans-autophosphorylation by kinase-dead Plk4, which then shields endogenous Plk4 from recognition by beta TrCP. We conclude that active Plk4 promotes its own degradation by catalyzing beta TrCP binding through trans-autophosphorylation (phosphorylation by the other kinase in the dimer) within homodimers.