Src regulates amino acid-mediated mTORC1 activation by disrupting GATOR1-Rag GTPase interaction

Rituraj Pal, Michela Palmieri, Arindam Chaudhury, Tiemo Jürgen Klisch, Alberto di Ronza, Joel R. Neilson, George G. Rodney and Marco Sardiello ()
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Rituraj Pal: Texas Children’s Hospital
Michela Palmieri: Texas Children’s Hospital
Arindam Chaudhury: Baylor College of Medicine
Tiemo Jürgen Klisch: Texas Children’s Hospital
Alberto di Ronza: Texas Children’s Hospital
Joel R. Neilson: Baylor College of Medicine
George G. Rodney: Baylor College of Medicine
Marco Sardiello: Texas Children’s Hospital

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract 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.

Date: 2018
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DOI: 10.1038/s41467-018-06844-4

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