DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy.
DEPTOR, an mTOR inhibitor, is a physiological substrate of SCF(βTrCP) E3 ubiquitin ligase and regulates survival and autophagy.
复制标题
DOI：
10.1016/j.molcel.2011.08.029
复制
发表时间：
2011-10-21
期刊：
影响因子：
16
通讯作者：
Sun Y
中科院分区：
文献类型：
--
作者：
Zhao Y;Xiong X;Sun Y
DEPTOR是mTORC 1和mTORC 2的抑制剂，通过泛素-蛋白酶体途径被未知的E3泛素连接酶降解。本文报道了DEPTOR是SCFβTrCP E3连接酶靶向降解的生理底物。在生长因子刺激后，RSK 1和S6 K1激酶被激活以磷酸化DEPTOR，然后通过其降解决定子序列被F-box蛋白βTrCP识别，随后被SCF E3泛素化和降解。内源性DEPTOR水平受βTrCP负调控。DEPTOR半衰期因βTrCP而缩短，但因βTrCP显性失活突变体、RSK 1/S6 K1抑制和βTrCP降解决定子位点突变而延长。在生物学上，βTrCP敲低后的DEPTOR积累使癌细胞中的mTORC 1失活并激活AKT，从而赋予对雷帕霉素和紫杉醇的抗性。此外，DEPTOR在葡萄糖剥夺和mTOR抑制后积累，以诱导自噬。因此，βTrCP-DEPTOR-mTOR介导调节细胞存活和自噬。
DEPTOR, an inhibitor of mTORC1 and mTORC2, is degraded via ubiquitin-proteasome pathway by an unknown E3 ubiquitin ligase. Here we report that DEPTOR is a physiological substrate of SCFβTrCP E3 ligase for targeted degradation. Upon growth factor stimulation, RSK1 and S6K1 kinases are activated to phosphorylate DEPTOR, which is then recognized by the F-box protein, βTrCP via its degron sequence for subsequent ubiquitination and degradation by SCF E3. Endogenous DEPTOR levels are negatively regulated by βTrCP. DEPTOR half-life is shortened by βTrCP but extended by a dominant negative mutant of βTrCP, by RSK1/S6K1 inhibition, and by βTrCP degron site mutations. Biologically, DEPTOR accumulation upon βTrCP knockdown inactivates mTORC1 and activates AKT in cancer cells to confer resistance to rapamycin and paclitaxel. Furthermore, DEPTOR accumulates upon glucose deprivation and mTOR inhibition, to induce autophagy. Thus, βTrCP-DEPTOR-mTOR intertwine to regulate cell survival and autophagy.
登录
查看更多内容
影响因子：
16
作者：
Dehan, Elinor;Bassermann, Florian;Guardavaccaro, Daniele;Vasiliver-Shamis, Gaia;Cohen, Michael;Lowes, Kym N.;Dustin, Michael;Huang, David C. S.;Taunton, Jack;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
7.5
作者：
Efeyan A;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
56.9
作者：
Dorrello, N. Valerio;Peschiaroli, Angelo;Pagano, Michele
通讯作者：
Pagano, Michele
影响因子：
64.5
作者：
Peterson TR;Laplante M;Thoreen CC;Sancak Y;Kang SA;Kuehl WM;Gray NS;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
7.8
作者：
Gu, Qingyang;Bowden, G. Tim;Normolle, Daniel;Sun, Yi
通讯作者：
Sun, Yi