Human NDR Kinases Control G1/S Cell Cycle Transition by Directly Regulating p21 Stability
Human NDR Kinases Control G1/S Cell Cycle Transition by Directly Regulating p21 Stability
复制标题
DOI：
10.1128/mcb.01216-10
复制
发表时间：
2011-04-01
影响因子：
5.3
通讯作者：
Hemmings, Brian A.
中科院分区：
文献类型：
--
作者：
Cornils, Hauke;Kohler, Reto S.;Hemmings, Brian A.
细胞周期的G(1)期是内部和外部信号的重要积分器，允许细胞决定是增殖、分化还是死亡。多种蛋白激酶，其中包括细胞周期蛋白依赖性蛋白激酶(CDK)、对照G(1)期进展和S期进入。通过调节河马通路组件MST1和MST2下游的细胞凋亡、中心体复制和有丝分裂染色体排列，哺乳动物的NDR激酶被认为在细胞周期依赖的过程中发挥作用。虽然它们在生化调节和上游信号通路方面都有很好的特征，但哺乳动物NDR激酶下游的信号机制仍然很大程度上是未知的。我们在这里确定了人类NDR在调节G(1)/S转变中的作用。在G(1)期，NDR激酶被第三个MST激酶(MST3)激活。值得注意的是，干扰NDR和MST3激酶的表达会导致G(1)期停滞和随后的增殖缺陷。此外，我们还描述了NDR激酶调节细胞周期进程的第一个下游信号机制。我们的发现表明，NDR激酶通过直接磷酸化来控制细胞周期蛋白-CDK抑制蛋白p21的蛋白稳定性。这些发现建立了一个新的MST3-ndr-p21轴，作为哺乳动物细胞G(1)/S进展的重要调节因子。
The G(1) phase of the cell cycle is an important integrator of internal and external cues, allowing a cell to decide whether to proliferate, differentiate, or die. Multiple protein kinases, among them the cyclin-dependent kinases (Cdks), control G(1)-phase progression and S-phase entry. With the regulation of apoptosis, centrosome duplication, and mitotic chromosome alignment downstream of the HIPPO pathway components MST1 and MST2, mammalian NDR kinases have been implicated to function in cell cycle-dependent processes. Although they are well characterized in terms of biochemical regulation and upstream signaling pathways, signaling mechanisms downstream of mammalian NDR kinases remain largely unknown. We identify here a role for human NDR in regulating the G(1)/S transition. In G(1) phase, NDR kinases are activated by a third MST kinase (MST3). Significantly, interfering with NDR and MST3 kinase expression results in G(1) arrest and subsequent proliferation defects. Furthermore, we describe the first downstream signaling mechanisms by which NDR kinases regulate cell cycle progression. Our findings suggest that NDR kinases control protein stability of the cyclin-Cdk inhibitor protein p21 by direct phosphorylation. These findings establish a novel MST3-NDR-p21 axis as an important regulator of G(1)/S progression of mammalian cells.