DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.
DEPTOR is an mTOR inhibitor frequently overexpressed in multiple myeloma cells and required for their survival.
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DOI：
10.1016/j.cell.2009.03.046
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发表时间：
2009-05-29
期刊：
影响因子：
64.5
通讯作者：
Sabatini DM
中科院分区：
文献类型：
--
作者：
Peterson TR;Laplante M;Thoreen CC;Sancak Y;Kang SA;Kuehl WM;Gray NS;Sabatini DM
mTORC1和mTORC2通路调节细胞生长、增殖和存活。我们鉴定出DEPTOR（也称为DEPDC6）是一种与mTOR相互作用的蛋白质，其表达受mTORC1和mTORC2负调控。DEPTOR缺失会激活S6K1、Akt和SGK1，促进细胞生长和存活，并激活mTORC1和mTORC2激酶活性。DEPTOR过表达会抑制S6K1，但通过解除从mTORC1到PI3K信号传导的反馈抑制，会激活Akt。与许多人类癌症中mTORC1和mTORC2通路被激活一致，DEPTOR在大多数癌症中表达较低。令人惊讶的是，在一部分存在细胞周期蛋白D1/D3或c - MAF/MAFB易位的多发性骨髓瘤中，DEPTOR高度过表达。在这些细胞中，高DEPTOR表达对于维持PI3K和Akt的激活是必要的，并且DEPTOR水平的降低会导致细胞凋亡。因此，我们鉴定出一种新的与mTOR相互作用的蛋白质，其在多发性骨髓瘤细胞中的失调性过表达代表了一种激活PI3K/Akt信号传导和促进细胞存活的新机制。
The mTORC1 and mTORC2 pathways regulate cell growth, proliferation, and survival. We identify DEPTOR, also called DEPDC6, as an mTOR-interacting protein whose expression is negatively regulated by mTORC1 and mTORC2. Loss of DEPTOR activates S6K1, Akt, and SGK1; promotes cell growth and survival; and activates mTORC1 and mTORC2 kinase activities. DEPTOR overexpression suppresses S6K1 but, by relieving feedback inhibition from mTORC1 to PI3K signaling, activates Akt. Consistent with many human cancers having activated mTORC1 and mTORC2 pathways, DEPTOR expression is low in most cancers. Surprisingly, DEPTOR is highly overexpressed in a subset of Multiple Myelomas harboring Cyclin D1/D3 or c-MAF/MAFB translocations. In these cells, high DEPTOR expression is necessary to maintain PI3K and Akt activation and a reduction in DEPTOR levels leads to apoptosis. Thus, we identify a novel mTOR-interacting protein whose deregulated overexpression in Multiple Myeloma cells represents a new mechanism for activating PI3K/Akt signaling and promoting cell survival.
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