Negative regulation of mTOR activation by diacylglycerol kinases
Negative regulation of mTOR activation by diacylglycerol kinases
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DOI：
10.1182/blood-2010-08-300731
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发表时间：
2011-04-14
期刊：
影响因子：
20.3
通讯作者：
Zhong, Xiao-Ping
中科院分区：
文献类型：
--
作者：
Gorentla, Balachandra K.;Wan, Chi-Keung;Zhong, Xiao-Ping
TCR的参与诱导T细胞活化，其引发多种特征性变化，例如细胞大小增加、细胞分裂以及细胞因子和其他效应分子的产生。哺乳动物雷帕霉素靶蛋白（mTOR）调节蛋白质合成、转录、细胞存活和自噬。mTOR在T细胞活化和效应子/记忆分化中的关键作用已经使用化学抑制剂或通过T细胞中mTOR的遗传消融来揭示。然而，mTOR信号传导和TCR下游的其他信号传导级联之间的联系尚不清楚。我们证明，二酰基甘油（DAG）和TCR接合通过激活Ras-有丝分裂原激活蛋白激酶/细胞外信号调节激酶1/2（Mek 1/2）-细胞外信号调节激酶1/2（Erk 1/2）-激活蛋白1（AP-1），激活mTOR复合物1和2中的信号传导，统称为Ras-Mek 1/2-Erk 1/2-AP-1途径。RasGRP 1的缺乏或Mek 1/2活性的抑制显著降低TCR诱导的mTOR活化，而组成型活性Ras或Mek 1促进mTOR活化。虽然组成型活性Akt促进TCR诱导的mTOR活化，但这种活化被Mek 1/2抑制减弱。我们进一步证明了终止DAG介导的信号传导的DAG激酶（DGKs）α和ζ通过抑制Ras-Mek 12-Erk/12途径协同抑制TCR诱导的mTOR活化。这些观察结果为mTOR激活的调节提供了新的见解。（血。2011;117（15）：4022-4031）
The engagement of TCR induces T-cell activation, which initiates multiple characteristic changes such as increase in cell size, cell division, and the production of cytokines and other effector molecules. The mammalian target of rapamycin (mTOR) regulates protein synthesis, transcription, cell survival, and autophagy. Critical roles of mTOR in T-cell activation and effector/memory differentiation have been revealed using chemical inhibitors or by genetic ablation of mTOR in T cells. However, the connection between mTOR signaling and other signaling cascades downstream of TCR is unclear. We demonstrate that diacylglycerol (DAG) and TCR engagement activate signaling in both mTOR complexes 1 and 2 through the activation of the Ras-mitogen-activated protein kinase/extracellular signal-regulated kinase 1/2 (Mek1/2)-extracellular signal-regulated kinase 1/2 (Erk1/2)-activator protein 1 (AP-1), known collectively as the Ras-Mek1/2-Erk1/2-AP-1 pathway. Deficiency of RasGRP1 or inhibition of Mek1/2 activity drastically decreases TCR-induced mTOR activation, whereas constitutively active Ras or Mek1 promotes mTOR activation. Although constitutively active Akt promotes TCR-induced mTOR activation, such activation is attenuated by Mek1/2 inhibition. We demonstrated further that DAG kinases (DGKs) alpha and zeta, which terminate DAG-mediated signaling, synergistically inhibit TCR-induced mTOR activation by inhibiting the Ras-Mek1/2-Erk/12 pathway. These observations provide novel insights into the regulation of mTOR activation. (Blood. 2011;117(15):4022-4031)