Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction.
Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction.
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DOI：
10.1038/s41467-018-06844-4
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发表时间：
2018-10-19
影响因子：
16.6
通讯作者：
Sardiello M
中科院分区：
文献类型：
--
作者：
Pal R;Palmieri M;Chaudhury A;Klisch TJ;di Ronza A;Neilson JR;Rodney GG;Sardiello M
雷帕霉素复合物1（mTORC 1）的机制靶点调节细胞存活和自噬，其活性受氨基酸可用性调节。Rag GTP酶-GATOR 1相互作用在不存在氨基酸的情况下抑制mTORC 1，并且GATOR 1释放和RagA/B的激活在存在氨基酸的情况下促进mTORC 1活性。然而，在Rag-GATOR 1相互作用中发挥作用的因素仍然缺乏特征。在这里，我们表明，酪氨酸激酶Src是至关重要的氨基酸介导的激活mTORC 1。Src通过促进GATOR 1从Rag上解离而作用于Rag GTP酶的上游，从而决定mTORC 1在溶酶体表面的募集和活化。因此，Src/mTORC 1的氨基酸介导的调节调节自噬和细胞大小扩增。最后，Src超活化在mTORC 1的活化中覆盖氨基酸信号传导。这些结果揭示了许多癌症类型中通路失调的潜在机制。mTORC 1的促生长活性通过Rag GTP酶通过氨基酸可用性调节。在这里，作者通过破坏Rag GTP酶-GATOR 1复合物和mTORC 1在溶酶体表面的活化，证明了Src依赖性控制细胞大小和自噬。
The mechanistic target of rapamycin complex 1 (mTORC1) regulates cell survival and autophagy, and its activity is regulated by amino acid availability. Rag GTPase-GATOR1 interactions inhibit mTORC1 in the absence of amino acids, and GATOR1 release and activation of RagA/B promotes mTORC1 activity in the presence of amino acids. However, the factors that play a role in Rag-GATOR1 interaction are still poorly characterized. Here, we show that the tyrosine kinase Src is crucial for amino acid-mediated activation of mTORC1. Src acts upstream of the Rag GTPases by promoting dissociation of GATOR1 from the Rags, thereby determining mTORC1 recruitment and activation at the lysosomal surface. Accordingly, amino acid-mediated regulation of Src/mTORC1 modulates autophagy and cell size expansion. Finally, Src hyperactivation overrides amino acid signaling in the activation of mTORC1. These results shed light on the mechanisms underlying pathway dysregulation in many cancer types. The growth-promoting activity of mTORC1 is regulated by amino acid availability via the Rag GTPases. Here, the authors demonstrate Src-dependent control of cell size and autophagy through disruption of the Rag GTPase–GATOR1 complex and mTORC1 activation at the lysosomal surface.
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影响因子：
64.8
作者：
Lee, Jae Man;Wagner, Martin;Xiao, Rui;Kim, Kang Ho;Feng, Dan;Lazar, Mitchell A.;Moore, David D.
通讯作者：
Moore, David D.
影响因子：
8.8
作者：
Chantranupong L;Wolfson RL;Orozco JM;Saxton RA;Scaria SM;Bar-Peled L;Spooner E;Isasa M;Gygi SP;Sabatini DM
通讯作者：
Sabatini DM
影响因子：
64.5
作者：
Demetriades C;Doumpas N;Teleman AA
通讯作者：
Teleman AA
影响因子：
5.3
作者：
Basu, Nirmalya;Bhandari, Rashna;Visweswariah, Sandhya S.
通讯作者：
Visweswariah, Sandhya S.
DOI：
10.1126/science.1199498
发表时间：
2011-06-10
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Hsu PP;Kang SA;Rameseder J;Zhang Y;Ottina KA;Lim D;Peterson TR;Choi Y;Gray NS;Yaffe MB;Marto JA;Sabatini DM
通讯作者：
Sabatini DM