title: K63 polyubiquitination and activation of mTOR by the p62-TRAF6 complex in nutrient-activated cells.
abstract: The ability of cells to respond to changes in nutrient availability is critical for an adequate control of metabolic homeostasis. Mammalian target of rapamycin complex 1 (mTORC1) is a central complex kinase in these processes. The signaling adaptor p62 binds raptor, and integral component of the mTORC1 pathway. p62 interacts with TNF receptor associated factor 6 (TRAF6) and is required for mTORC1 translocation to the lysosome and its subsequent activation. Here we show that TRAF6 is recruited to and activates mTORC1 through p62 in amino acid-stimulated cells. We also show that TRAF6 is necessary for the translocation of mTORC1 to the lysosomes and that the TRAF6-catalyzed K63 ubiquitination of mTOR regulates mTORC1 activation by amino acids. TRAF6, through its interaction with p62 and activation of mTORC1, modulates autophagy and is an important mediator in cancer cell proliferation. Interfering with the p62-TRAF6 interaction serves to modulate autophagy and nutrient sensing.
authors.affiliation: Sanford-Burnham Medical Research Institute, 10901 North Torrey Pines Road, La Jolla, CA 92037, USA.
authors.forename: Juan F
authors.initials: JF
authors.lastname: Linares
authors.forename: Angeles
authors.initials: A
authors.lastname: Duran
authors.forename: Tomoko
authors.initials: T
authors.lastname: Yajima
authors.forename: Manolis
authors.initials: M
authors.lastname: Pasparakis
authors.forename: Jorge
authors.initials: J
authors.lastname: Moscat
authors.forename: Maria T
authors.initials: MT
authors.lastname: Diaz-Meco
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D001343:Autophagy / Q000502:physiology; D001692:Biological Transport; D002460:Cell Line; D049109:Cell Proliferation; D004789:Enzyme Activation; D057809:HEK293 Cells; D006360:Heat-Shock Proteins / Q000378:metabolism*; D006801:Humans; D008247:Lysosomes / Q000378:metabolism; D000076222:Mechanistic Target of Rapamycin Complex 1; D051379:Mice; D018345:Mice, Knockout; D046912:Multiprotein Complexes / Q000378:metabolism*; D009154:Mutation; D016328:NF-kappa B / Q000378:metabolism; D034622:RNA Interference; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; D048029:TNF Receptor-Associated Factor 6 / Q000235:genetics / Q000378:metabolism*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism*; D054875:Ubiquitination
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D006360:Heat-Shock Proteins; D046912:Multiprotein Complexes; D016328:NF-kappa B; D034741:RNA, Small Interfering; D000071456:Sequestosome-1 Protein; C101343:Sqstm1 protein, mouse; D048029:TNF Receptor-Associated Factor 6; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases
references.citation: Cell. 2010 Nov 24;143(5):682-5
references.pmid: 21111229
references.citation: Science. 2009 Aug 28;325(5944):1134-8
references.pmid: 19713527
references.citation: J Biol Chem. 2007 Feb 9;282(6):4102-12
references.pmid: 17135271
references.citation: Science. 2008 Jun 13;320(5882):1496-501
references.pmid: 18497260
references.citation: Nature. 2010 Jun 17;465(7300):942-6
references.pmid: 20526321
references.citation: Nature. 2002 Jul 25;418(6896):443-7
references.pmid: 12140561
references.citation: Science. 2008 Sep 12;321(5895):1499-502
references.pmid: 18787170
references.citation: EMBO Rep. 2009 Aug;10(8):804
references.pmid: 19648954
references.citation: Nat Rev Mol Cell Biol. 2013 Mar;14(3):133-9
references.pmid: 23361334
references.citation: Mol Cell. 2011 Oct 21;44(2):304-16
references.pmid: 22017876
references.citation: EMBO J. 2006 Aug 9;25(15):3524-33
references.pmid: 16874300
references.citation: Cell. 2012 Apr 13;149(2):274-93
references.pmid: 22500797
references.citation: Nat Cell Biol. 2013 Apr;15(4):406-16
references.pmid: 23524951
references.citation: Sci Signal. 2010 May 25;3(123):ra42
references.pmid: 20501938
references.citation: Mol Cell. 2011 Oct 7;44(1):134-46
references.pmid: 21981924
references.citation: Trends Endocrinol Metab. 2011 Mar;22(3):94-102
references.pmid: 21269838
references.citation: Nat Cell Biol. 2008 Aug;10(8):935-45
references.pmid: 18604198
references.citation: Genes Dev. 2008 Apr 1;22(7):866-71
references.pmid: 18381890
references.citation: Cancer Cell. 2008 Apr;13(4):343-54
references.pmid: 18394557
references.citation: Immunol Rev. 2012 Mar;246(1):95-106
references.pmid: 22435549
references.citation: Mol Cell. 2008 May 23;30(4):403-14
references.pmid: 18498745
references.citation: J Clin Invest. 2011 Oct;121(10):4095-105
references.pmid: 21911935
references.citation: Cell. 2009 Jun 12;137(6):1001-4
references.pmid: 19524504
references.citation: Science. 2011 Nov 4;334(6056):678-83
references.pmid: 22053050
references.citation: Biochem Biophys Res Commun. 2008 Jul 4;371(3):521-4
references.pmid: 18457658
references.citation: Mol Cell. 2013 Feb 7;49(3):379-87
references.pmid: 23395268
references.citation: Trends Biochem Sci. 2007 Feb;32(2):95-100
references.pmid: 17174552
references.citation: Mol Cell. 2005 Oct 28;20(2):301-12
references.pmid: 16246731
references.citation: Nature. 2013 Feb 14;494(7436):201-6
references.pmid: 23364696
references.citation: Genes Dev. 2011 Mar 1;25(5):460-70
references.pmid: 21317241
references.citation: Dev Cell. 2004 Feb;6(2):303-9
references.pmid: 14960283
references.citation: Cell. 2002 Jul 26;110(2):177-89
references.pmid: 12150926
references.citation: Nature. 2010 Feb 18;463(7283):899-905
references.pmid: 20164920
references.citation: Cell. 2002 Jul 26;110(2):163-75
references.pmid: 12150925
references.citation: EMBO J. 2000 Apr 3;19(7):1576-86
references.pmid: 10747026
references.citation: J Biol Chem. 2007 Aug 17;282(33):24131-45
references.pmid: 17580304
references.citation: Cell. 2010 Apr 16;141(2):290-303
references.pmid: 20381137
references.citation: J Cell Biol. 2005 Nov 21;171(4):603-14
references.pmid: 16286508
references.citation: Cell. 2011 Nov 11;147(4):724-7
references.pmid: 22078874
references.citation: J Biol Chem. 2005 Oct 21;280(42):35625-9
references.pmid: 16079148
references.citation: Nature. 2000 Nov 30;408(6812):600-5
references.pmid: 11117749
references.citation: Cancer Cell. 2012 Jan 17;21(1):105-20
references.pmid: 22264792
references.citation: Nat Rev Mol Cell Biol. 2011 Jan;12(1):21-35
references.pmid: 21157483
references.citation: EMBO Rep. 2009 Aug;10(8):866-72
references.pmid: 19557001
references.citation: EMBO Rep. 2012 Feb 01;13(2):121-8
references.pmid: 22240970
references.citation: Mol Cell. 2011 Oct 21;44(2):290-303
references.pmid: 22017875
references.citation: J Biol Chem. 2001 Mar 9;276(10):7246-57
references.pmid: 11073942
references.citation: Mol Cell Biol. 1998 May;18(5):3069-80
references.pmid: 9566925
references.citation: Cell. 2000 Oct 13;103(2):351-61
references.pmid: 11057907
references.citation: Mol Cell Biol. 2012 Jan;32(1):2-11
references.pmid: 22025673
references.citation: Cell. 2012 Sep 14;150(6):1196-208
references.pmid: 22980980