The CASTOR proteins are arginine sensors for the mTORC1 pathway

By Lynne Chantranupong, Sonia M. Scaria, R. A. Saxton, Melanie P. Gygi, K. Shen, Gregory A. Wyant, Tim Wang, J. W. Harper, Steven P. Gygi, David M. Sabatini. Cell, 2016

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Amino acids signal to the mTOR complex I (mTORC1) growth pathway through the Rag GTPases. Multiple distinct complexes regulate the Rags, including GATOR1, a GTPase activating protein (GAP), and GATOR2, a positive regulator of unknown molecular function. Arginine stimulation of cells activates mTORC1, but how it is sensed is not well understood. Recently, SLC38A9 was identified as a putative lysosomal arginine sensor required for arginine to activate mTORC1 but how arginine deprivation represses mTORC1 is unknown. Here, we show that CASTOR1, a previously uncharacterized protein, interacts with GATOR2 and is required for arginine deprivation to inhibit mTORC1. CASTOR1 homodimerizes and can also heterodimerize with the related protein, CASTOR2. Arginine disrupts the CASTOR1-GATOR2 complex by binding to CASTOR1 with a dissociation constant of ~30 μM, and its arginine-binding capacity is required for arginine to activate mTORC1 in cells. Collectively, these results establish CASTOR1 as an arginine sensor for the mTORC1 pathway.

Subfields: Molecular Biology, Physiology

View Paper: https://www.semanticscholar.org/paper/4076ffaab709919520cd51c6ebc7031fc359a71e

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Citations in the corpus

Nutrient sensing and TOR signaling in yeast and mammals (2017, positive): “Based on genetic experiments, it has been suggested that CASTOR1 and SLC38A9 regulate mTORC1 activation by arginine via parallel mechanisms (Chantranupong et al , 2016).”
From Krebs to Clinic: Glutamine Metabolism to Cancer Therapy (2016, background): “BPTES inhibition of hGA(124-551), a truncated form of human kidneytype glutaminase.”
Metabolomics for Investigating Physiological and Pathophysiological Processes. (2019, background): “In addition to their role as insulin secretagogues, it is also known that arginine, lysine, glutamine, and leucine all activate mTOR (77, 104, 410).”
mTOR Signaling in Growth, Metabolism, and Disease (2017, background): “Much like Sestrin2, CASTOR1 binds and inhibits GATOR2 in the absence of arginine, and dissociates upon argininebinding to enable theactivation ofmTORC1 (Chantranupong et al., 2016; Saxton et al., 2016b).”
A systems study reveals concurrent activation of AMPK and mTOR by amino acids (2016, background): “Here, the branched-chain aa leucine, as well as glutamine and arginine deserve particular attention, as they all have been identiﬁed as being important in the regulation of the mTOR network 5,62,63 .”