Hergovich Alexander, Lamla Stefan, Nigg Erich A, Hemmings Brian A
Friedrich Miescher Institute for Biomedical Research, Maulbeerstrasse 66, CH-4058 Basel, Switzerland.
Mol Cell. 2007 Feb 23;25(4):625-34. doi: 10.1016/j.molcel.2007.01.020.
Human NDR kinases are upregulated in some cancer types, yet their functions still remain undefined. Here, we report the first known function of a mammalian NDR kinase by demonstrating that human NDR directly contributes to centrosome duplication. A subpopulation of endogenous NDR localizes to centrosomes in a cell-cycle-dependent manner. Overexpression of NDR resulted in centrosome overduplication in a kinase-activity-dependent manner, while expression of kinase-dead NDR or depletion of NDR by small interfering RNA (siRNA) negatively affected centrosome duplication. By targeting NDR to the centrosome, we show that the centrosomal pool of NDR is sufficient to generate supernumerary centrosomes. Furthermore, our data indicate that NDR-driven centrosome duplication requires Cdk2 activity and that Cdk2-induced centrosome amplification is affected upon reduction of NDR activity. Overall, considering that centrosome overduplication is linked to cellular transformation, our observations may also provide a molecular link between mammalian NDR kinases and cancer.
人类NDR激酶在某些癌症类型中上调，但其功能仍不明确。在此，我们通过证明人类NDR直接促进中心体复制，报道了哺乳动物NDR激酶的首个已知功能。内源性NDR的一个亚群以细胞周期依赖性方式定位于中心体。NDR的过表达以激酶活性依赖性方式导致中心体过度复制，而激酶失活的NDR的表达或通过小干扰RNA（siRNA）耗尽NDR则对中心体复制产生负面影响。通过将NDR靶向中心体，我们表明中心体池中的NDR足以产生多余的中心体。此外，我们的数据表明，NDR驱动的中心体复制需要Cdk2活性，并且当NDR活性降低时，Cdk2诱导的中心体扩增会受到影响。总体而言，鉴于中心体过度复制与细胞转化有关，我们的观察结果也可能提供哺乳动物NDR激酶与癌症之间的分子联系。
