title: Ragulator-Rag complex targets mTORC1 to the lysosomal surface and is necessary for its activation by amino acids.
abstract: The mTORC1 kinase promotes growth in response to growth factors, energy levels, and amino acids, and its activity is often deregulated in disease. The Rag GTPases interact with mTORC1 and are proposed to activate it in response to amino acids by promoting mTORC1 translocation to a membrane-bound compartment that contains the mTORC1 activator, Rheb. We show that amino acids induce the movement of mTORC1 to lysosomal membranes, where the Rag proteins reside. A complex encoded by the MAPKSP1, ROBLD3, and c11orf59 genes, which we term Ragulator, interacts with the Rag GTPases, recruits them to lysosomes, and is essential for mTORC1 activation. Constitutive targeting of mTORC1 to the lysosomal surface is sufficient to render the mTORC1 pathway amino acid insensitive and independent of Rag and Ragulator, but not Rheb, function. Thus, Rag-Ragulator-mediated translocation of mTORC1 to lysosomal membranes is the key event in amino acid signaling to mTORC1.
authors.affiliation: Whitehead Institute for Biomedical Research, 9 Cambridge Center, Cambridge, MA 02142, USA.
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Sancak
authors.forename: Liron
authors.initials: L
authors.lastname: Bar-Peled
authors.forename: Roberto
authors.initials: R
authors.lastname: Zoncu
authors.forename: Andrew L
authors.initials: AL
authors.lastname: Markhard
authors.forename: Shigeyuki
authors.initials: S
authors.lastname: Nada
authors.forename: David M
authors.initials: DM
authors.lastname: Sabatini
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000596:Amino Acids / Q000378:metabolism; D000818:Animals; D002460:Cell Line; D004330:Drosophila; D006801:Humans; D007425:Intracellular Membranes / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins / Q000378:metabolism; D008247:Lysosomes / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D000076222:Mechanistic Target of Rapamycin Complex 1; D008954:Models, Biological; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism; D046912:Multiprotein Complexes; D009154:Mutation; D009479:Neuropeptides / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D021381:Protein Transport; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D000076205:Ras Homolog Enriched in Brain Protein; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D000076223:Regulatory-Associated Protein of mTOR; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000596:Amino Acids; D047908:Intracellular Signaling Peptides and Proteins; C497811:LAMP2 protein, human; C485425:LAMTOR3 protein, human; D052119:Lysosomal-Associated Membrane Protein 2; D051907:Lysosomal Membrane Proteins; D046912:Multiprotein Complexes; D009479:Neuropeptides; D011506:Proteins; C490211:RHEB protein, human; C463659:RPTOR protein, human; D000076205:Ras Homolog Enriched in Brain Protein; D011994:Recombinant Proteins; D000076223:Regulatory-Associated Protein of mTOR; D014157:Transcription Factors; C546842:MTOR protein, human; D000076222:Mechanistic Target of Rapamycin Complex 1; D017346:Protein Serine-Threonine Kinases; D058570:TOR Serine-Threonine Kinases; D020559:Monomeric GTP-Binding Proteins
references.citation: Science. 1998 Sep 11;281(5383):1668-71
references.pmid: 9733512
references.citation: J Cell Biol. 2004 Nov 8;167(3):399-403
references.pmid: 15533996
references.citation: J Biochem. 2005 Mar;137(3):423-30
references.pmid: 15809346
references.citation: EMBO J. 1999 Jun 1;18(11):2991-3006
references.pmid: 10357812
references.citation: Mol Cell. 2009 Sep 11;35(5):563-73
references.pmid: 19748353
references.citation: J Biol Chem. 2005 Sep 23;280(38):32768-74
references.pmid: 16046393
references.citation: J Cell Sci. 1998 Jan;111 ( Pt 1):11-21
references.pmid: 9394008
references.citation: Dev Cell. 2002 Dec;3(6):803-14
references.pmid: 12479806
references.citation: J Cell Biol. 2006 Dec 18;175(6):861-8
references.pmid: 17178906
references.citation: J Cell Sci. 2009 Oct 15;122(Pt 20):3589-94
references.pmid: 19812304
references.citation: J Biol Chem. 2005 May 13;280(19):18717-27
references.pmid: 15772076
references.citation: Science. 2005 Feb 18;307(5712):1098-101
references.pmid: 15718470
references.citation: Curr Biol. 2000 Nov 2;10(21):R774-6
references.pmid: 11084347
references.citation: Nat Cell Biol. 2008 Aug;10(8):935-45
references.pmid: 18604198
references.citation: Dev Cell. 2006 Dec;11(6):859-71
references.pmid: 17141160
references.citation: J Cell Sci. 1994 Jun;107 ( Pt 6):1661-70
references.pmid: 7962206
references.citation: Mol Aspects Med. 2006 Oct-Dec;27(5-6):495-502
references.pmid: 16973206
references.citation: J Biol Chem. 2004 May 28;279(22):23422-30
references.pmid: 15016825
references.citation: Cancer Cell. 2007 Jul;12(1):9-22
references.pmid: 17613433
references.citation: J Biol Chem. 1995 Dec 1;270(48):28982-8
references.pmid: 7499430
references.citation: Science. 2008 Jun 13;320(5882):1496-501
references.pmid: 18497260
references.citation: Biochim Biophys Acta. 2009 Apr;1793(4):650-63
references.pmid: 18786576
references.citation: Mol Cell. 2007 Mar 23;25(6):903-15
references.pmid: 17386266
references.citation: EMBO J. 2009 Mar 4;28(5):477-89
references.pmid: 19177150
references.citation: J Biol Chem. 1997 Apr 18;272(16):10608-15
references.pmid: 9099708
references.citation: Science. 1999 Nov 26;286(5445):1741-4
references.pmid: 10576742
references.citation: Nat Med. 2007 Jan;13(1):38-45
references.pmid: 17195838
references.citation: J Cell Biol. 2001 Feb 19;152(4):765-76
references.pmid: 11266467
references.citation: Biochem Biophys Res Commun. 2006 Jun 9;344(3):869-80
references.pmid: 16631613
references.citation: Mol Cell. 2005 Jul 1;19(1):15-26
references.pmid: 15989961
references.citation: Oncogene. 2006 Feb 2;25(5):657-64
references.pmid: 16170341
references.citation: Nat Cell Biol. 2006 Jul;8(7):657-67
references.pmid: 16732272
references.citation: Mol Biol Cell. 2009 Mar;20(5):1565-75
references.pmid: 19144819
references.citation: Nat Rev Mol Cell Biol. 2007 Aug;8(8):622-32
references.pmid: 17637737
references.citation: J Biol Chem. 2001 Mar 9;276(10):7246-57
references.pmid: 11073942
references.citation: Cell. 1990 Jul 27;62(2):317-29
references.pmid: 2115402
references.citation: Bioessays. 2006 Feb;28(2):146-56
references.pmid: 16435292