title: Amino acid-dependent NPRL2 interaction with Raptor determines mTOR Complex 1 activation.
abstract: We assign a new function to a tumor suppressor NPRL2 that activates the mTOR complex 1 (mTORC1) activity. The positive regulation of mTORC1 activity by NPRL2 is mediated through NPRL2 interaction with Raptor. While NPRL2 interacts with Rag GTPases, RagD in particular, to interfere with mTORC1 activity in amino acid scarcity, NPRL2 interacts with Raptor in amino acid sufficiency to activate mTORC1. A reciprocal relationship exists between NPRL2 binding to Rag GTPases and Raptor. NPRL2 majorly locates in the lysosomal membranes and has a higher binding affinity to the dominant negative mutant heterodimer of RagA(GDP)/RagD(GTP) that inactivates mTORC1. However, the binding affinity of NPRL2 with Raptor is much less pronounced in cells expressing the dominant negative mutant heterodimer of RagA(GDP)/RagD(GTP) than in cells expressing the dominant positive mutant heterodimer, RagA(GTP)/RagD(GDP). The positive effect of NPRL2 on TORC1 pathway was also evidenced in Drosophila animal model. Here, we propose a 'seesaw' model in which the interactive behavior of NPRL2 with Raptor determines mTORC1 activation by amino acid signaling in animal cells.
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Sang Su
authors.initials: SS
authors.lastname: Kwak
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Kyung Hwa
authors.initials: KH
authors.lastname: Kang
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Seyun
authors.initials: S
authors.lastname: Kim
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Seoeun
authors.initials: S
authors.lastname: Lee
authors.affiliation: Department of Dermatology, School of Medicine, Chungnam National University, Daejeon 305-764, South Korea; Dermatology Lab., SKINMED Corporation, Daejeon 305-500, South Korea.
authors.forename: Jeung-Hoon
authors.initials: JH
authors.lastname: Lee
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea.
authors.forename: Jin Woo
authors.initials: JW
authors.lastname: Kim
authors.affiliation: Department of Oriental Medicine, Daegu Haany University, Daegu 705-060, South Korea.
authors.forename: Boohyeong
authors.initials: B
authors.lastname: Byun
authors.affiliation: Department of Pharmaceutical Sciences, Washington State University, Spokane, WA 99210, USA.
authors.forename: Gary G
authors.initials: GG
authors.lastname: Meadows
authors.affiliation: Department of Biological Sciences, Korea Advanced Institute of Science and Technology, Daejeon 305-701, South Korea; Dermatology Lab., SKINMED Corporation, Daejeon 305-500, South Korea. Electronic address: cojoe@kaist.ac.kr.
authors.forename: Cheol O
authors.initials: CO
authors.lastname: Joe
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000596:Amino Acids / Q000378:metabolism*; D020690:GTPase-Activating Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D000076222:Mechanistic Target of Rapamycin Complex 1; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes / Q000378:metabolism*; D011485:Protein Binding; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D020690:GTPase-Activating Proteins; D046912:Multiprotein Complexes; C492816:NPRL2 protein, human; C543618:NPRL3 protein, human; C463659:RPTOR protein, human; D000076223:Regulatory-Associated Protein of mTOR; D025521:Tumor Suppressor Proteins; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins
keywords: Amino acids; Lysosome; NPRL2; Rag GTPases; Raptor; mTOR complex 1 (mTORC1)