biostudies-literatureChantranupong LNIAID NIH HHSUS NIHNHGRI NIH HHSNCI NIH HHSNIHJohn Reed UROP FundNational Defense Science & Engineering Graduate FellowshipDepartment of DefenseNIGMS NIH HHS153-164https://www.ebi.ac.uk/biostudies/studies/S-EPMC4808398biostudies-literatureUnknown165(1)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 CellThe CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway.PMC4808398R01 GM095567R01 AI047389R01CA103866GM095567U41 HG006673R01 CA103866R37 AI047389AI47389)F31 CA189437F31 CA180271T32 GM007287AI47389P30 CA014051W81XWH-07-0448Harper JWSabatini DMChantranupong LShen KWyant GAWang TSaxton RAGygi SPScaria SMGygi MPfalseThe CASTOR Proteins Are Arginine Sensors for the mTORC1 Pathway.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 2016-01-01T00:00:00Z2016 Mar2025-04-04T00:15:05.571Z2019-03-27T03:10:21ZS-EPMC48083982697205310.1016/j.cell.2016.02.035