The Death Effector Domain-containing DEDD Supports S6K1 Activity via Preventing Cdk1-dependent Inhibitory Phosphorylation
The Death Effector Domain-containing DEDD Supports S6K1 Activity via Preventing Cdk1-dependent Inhibitory Phosphorylation
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DOI：
10.1074/jbc.m808598200
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发表时间：
2009-02-20
影响因子：
4.8
通讯作者：
Miyazaki, Toru
中科院分区：
文献类型：
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作者：
Kurabe, Nobuya;Arai, Satoko;Miyazaki, Toru
细胞周期调控和对营养物质和生长因子的生化反应是哺乳动物细胞大小的主要调控机制。最近，我们发现，死亡效应结构域包含DEDD阻碍有丝分裂的进展，通过抑制Cdk 1（细胞周期蛋白依赖性激酶1），从而保持在有丝分裂期细胞大小的增加。在这里，我们发现，DEDD还与S6激酶1（S6 K1），下游的磷脂酰肌醇3-激酶，并支持其活动，防止抑制磷酸化的S6 K1所带来的Cdk 1在有丝分裂期。DEDD-/-细胞显示出降低的S6 K1活性，始终表明Thr-389位点的活化磷酸化水平降低。此外，在DEDD-/-细胞和组织中，S6 K1 C末端的Cdk 1依赖性抑制性磷酸化水平增强。因此，与S6 K1（-/-）小鼠一样，DEDD-/-小鼠胰岛内的胰岛素质量减少，导致葡萄糖耐受不良。这些发现表明，DEDD通过在细胞分裂前维持S6 K1活性实现了一种新的细胞大小调节机制。我们的研究结果还表明，DEDD可能在葡萄糖稳态中具有重要作用，其缺陷可能参与2型糖尿病的发病机制。
Cell cycle regulation and biochemical responses upon nutrients and growth factors are the major regulatory mechanisms for cell sizing in mammals. Recently, we identified that the death effector domain-containing DEDD impedes mitotic progression by inhibiting Cdk1 (cyclin-dependent kinase 1) and thus maintains an increase of cell size during the mitotic phase. Here we found that DEDD also associates with S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase, and supports its activity by preventing inhibitory phosphorylation of S6K1 brought about by Cdk1 during the mitotic phase. DEDD-/- cells showed reduced S6K1 activity, consistently demonstrating decreased levels in activating phosphorylation at the Thr-389 site. In addition, levels of Cdk1-dependent inhibitory phosphorylation at the C terminus of S6K1 were enhanced in DEDD-/- cells and tissues. Consequently, as in S6K1(-/-) mice, the insulin mass within pancreatic islets was reduced in DEDD-/- mice, resulting in glucose intolerance. These findings suggest a novel cell sizing mechanism achieved by DEDD through the maintenance of S6K1 activity prior to cell division. Our results also suggest that DEDD may harbor important roles in glucose homeostasis and that its deficiency might be involved in the pathogenesis of type 2 diabetes mellitus.