The death effector domain-containing DEDD forms a complex with Akt and Hsp90, and supports their stability.
The death effector domain-containing DEDD forms a complex with Akt and Hsp90, and supports their stability.
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DOI：
10.1016/j.bbrc.2009.12.137
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发表时间：
2010-01-22
影响因子：
3.1
通讯作者：
Miyazaki, Toru
中科院分区：
文献类型：
--
作者：
Kurabe, Nobuya;Mori, Mayumi;Kurokawa, Jun;Taniguchi, Kaori;Aoyama, Hisatoshi;Atsuda, Kazuhiro;Nishijima, Akemi;Odawara, Nariaki;Harada, Saori;Nakashima, Katsuhiko;Arai, Satoko;Miyazaki, Toru
胰岛素分泌和葡萄糖转运是平衡葡萄糖稳态的主要机制。最近，我们发现含有死亡效应结构域的DEDD抑制细胞周期蛋白依赖性激酶1 （Cdk1）的功能，从而阻止磷脂酰肌醇3-激酶（PI3K）下游S6激酶1 （S6K1）的Cdk1依赖性抑制磷酸化，从而总体上维持S6K1的活性。本研究发现，DEDD与Akt和热休克蛋白90 （Hsp90）形成复合物，并支持这两种蛋白的稳定性。因此，在DEDD - / -小鼠中，骨骼肌和脂肪组织中的Akt蛋白水平降低，这干扰了胰岛素刺激下葡萄糖转运蛋白4 （GLUT4）的易位，导致葡萄糖在这些器官中的整合效率低下。有趣的是，对于S6K1的激活，抑制Cdk1参与了DEDD对Akt蛋白的稳定，因为通过siRNA表达或Cdk1抑制剂处理，DEDD−/−细胞中Cdk1的减少会增加Akt和Hsp90蛋白水平。通过支持胰岛素分泌（通过维持S6K1活性）和葡萄糖摄取（通过稳定Akt蛋白），DEDD在葡萄糖稳态中的多重参与可能表明ddd缺乏与2型糖尿病的发病机制有关。
Insulin secretion and glucose transport are the major mechanisms to balance glucose homeostasis. Recently, we found that the death effector domain-containing DEDD inhibits cyclin-dependent kinase 1 (Cdk1) function, thereby preventing Cdk1-dependent inhibitory phosphorylation of S6 kinase 1 (S6K1), downstream of phosphatidylinositol 3-kinase (PI3K), which overall results in maintenance of S6K1 activity. Here we newly show that DEDD forms a complex with Akt and heat-shock protein 90 (Hsp90), and supports the stability of both proteins. Hence, in DEDD−/− mice, Akt protein levels are diminished in skeletal muscles and adipose tissues, which interferes with the translocation of glucose transporter 4 (GLUT4) upon insulin stimulation, leading to inefficient incorporation of glucose in these organs. Interestingly, as for the activation of S6K1, suppression of Cdk1 is involved in the stabilization of Akt protein by DEDD, since diminishment of Cdk1 in DEDD−/− cells via siRNA expression or treatment with a Cdk1-inhibitor, increases both Akt and Hsp90 protein levels. Such multifaceted involvement of DEDD in glucose homeostasis by supporting both insulin secretion (via maintenance of S6K1 activity) and glucose uptake (via stabilizing Akt protein), may suggest an association of DEDD-deficiency with the pathogenesis of type 2 diabetes mellitus.
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