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.

中文翻译：

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Src通过破坏GATOR1-Rag GTPase相互作用来调节氨基酸介导的mTORC1活化。

雷帕霉素复合物1（mTORC1）的机械目标调节细胞存活和自噬，其活性受氨基酸可用性的调节。在没有氨基酸的情况下，Rag GTPase-GATOR1的相互作用会抑制mTORC1，而在存在氨基酸的情况下，GATOR1的释放和RagA / B的激活会促进mTORC1的活性。但是，在Rag-GATOR1相互作用中发挥作用的因素仍然不明确。在这里，我们表明酪氨酸激酶Src对于氨基酸介导的mTORC1激活至关重要。Src通过促进GATOR1与Rags的解离而在Rag GTPases上游起作用，从而确定溶酶体表面的mTORC1募集和激活。因此，氨基酸介导的Src / mTORC1调节可调节自噬和细胞大小扩展。最后，在mTORC1的激活中，Src过度激活会覆盖氨基酸信号。这些结果揭示了许多癌症类型中通路失调的潜在机制。