SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma
SCFFbxo9 and CK2 direct the cellular response to growth factor withdrawal via Tel2/Tti1 degradation and promote survival in multiple myeloma
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DOI：
10.1038/ncb2651
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发表时间：
2013-01-01
影响因子：
21.3
通讯作者：
Bassermann, Florian
中科院分区：
文献类型：
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作者：
Fernandez-Saiz, Vanesa;Targosz, Bianca-Sabrina;Bassermann, Florian
Tel 2（也称为Telo 2）和Tti 1蛋白控制哺乳动物PIKK的细胞丰度，是mTORC 1和mTORC 2的组成部分。在这里，我们报告说，Tel 2和Tti 1的靶向降解mTORC 1内的SCFFbxo 9泛素连接酶调节mTOR信号的生长因子的可用性。该过程由CK 2启动，CK 2在生长因子剥夺后易位至细胞质以介导Tel 2/Tti 1的mTORC 1特异性磷酸化。因此，mTORC 1失活以抑制细胞生长和蛋白质翻译，而反馈抑制的缓解激活PI（3）K/TORC 2/Akt通路以维持存活。值得注意的是，原发性人多发性骨髓瘤表现出高水平的Fbxo 9。在这种情况下，PI（3）K/TORC 2/Akt信号传导和多发性骨髓瘤细胞的存活依赖于Fbxo 9表达。因此，Tel 2和Tti 1蛋白的mTORC 1特异性降解代表了在多发性骨髓瘤中具有意义的中心mTOR调节机制，既促进了生存，又为具有高水平Fbxo 9表达的多发性骨髓瘤的特异性治疗提供了靶点。
The Tel2 (also known as Telo2) and Tti1 proteins control the cellular abundance of mammalian PIKKs and are integral components of mTORC1 and mTORC2. Here we report that Tel2 and Tti1 are targeted for degradation within mTORC1 by the SCFFbxo9 ubiquitin ligase to adjust mTOR signalling to growth factor availability. This process is primed by CK2, which translocates to the cytoplasm to mediate mTORC1-specific phosphorylation of Tel2/Tti1, subsequent to growth factor deprivation. As a consequence, mTORC1 is inactivated to restrain cell growth and protein translation whereas relief of feedback inhibition activates the PI(3)K/TORC2/Akt pathway to sustain survival. Significantly, primary human multiple myelomas exhibit high levels of Fbxo9. In this setting, PI(3)K/TORC2/Akt signalling and survival of multiple myeloma cells is dependent on Fbxo9 expression. Thus, mTORC1-specific degradation of the Tel2 and Tti1 proteins represents a central mTOR regulatory mechanism with implications in multiple myeloma, both in promoting survival and in providing targets for the specific treatment of multiple myeloma with high levels of Fbxo9 expression.