title: Activation of TORC1 transcriptional coactivator through MEKK1-induced phosphorylation.
abstract: CREB is a prototypic bZIP transcription factor and a master regulator of glucose metabolism, synaptic plasticity, cell growth, apoptosis, and tumorigenesis. Transducers of regulated CREB activity (TORCs) are essential transcriptional coactivators of CREB and an important point of regulation on which various signals converge. In this study, we report on the activation of TORC1 through MEKK1-mediated phosphorylation. MEKK1 potently activated TORC1, and this activation was independent of downstream effectors MEK1/MEK2, ERK2, JNK, p38, protein kinase A, and calcineurin. MEKK1 induced phosphorylation of TORC1 both in vivo and in vitro. Expression of the catalytic domain of MEKK1 alone in cultured mammalian cells sufficiently caused phosphorylation and subsequent activation of TORC1. MEKK1 physically interacted with TORC1 and stimulated its nuclear translocation. An activation domain responsive to MEKK1 stimulation was mapped to amino acids 431-650 of TORC1. As a physiological activator of CREB, interleukin 1alpha triggered MEKK1-dependent phosphorylation of TORC1 and its consequent recruitment to the cAMP response elements in the interleukin 8 promoter. Taken together, our findings suggest a new mechanism for regulated activation of TORC1 transcriptional coactivator and CREB signaling.
authors.affiliation: Department of Biochemistry and Department of Anatomy, The University of Hong Kong, Pokfulam, Hong Kong.
authors.forename: Yeung-Tung
authors.initials: YT
authors.lastname: Siu
authors.forename: Yick-Pang
authors.initials: YP
authors.lastname: Ching
authors.forename: Dong-Yan
authors.initials: DY
authors.lastname: Jin
mesh_terms: D019703:Calcineurin / Q000378:metabolism; D002467:Cell Nucleus / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D016209:Interleukin-8 / Q000235:genetics; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D048728:MAP Kinase Kinase Kinase 1 / Q000378:metabolism*; D010766:Phosphorylation; D010769:Phosphothreonine / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D021381:Protein Transport; D015534:Trans-Activators / Q000378:metabolism*; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D014158:Transcription, Genetic; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: C500984:CRTC1 protein, human; D016209:Interleukin-8; D015534:Trans-Activators; D014157:Transcription Factors; D010769:Phosphothreonine; D017868:Cyclic AMP-Dependent Protein Kinases; D048049:Extracellular Signal-Regulated MAP Kinases; D048031:JNK Mitogen-Activated Protein Kinases; D048051:p38 Mitogen-Activated Protein Kinases; D048728:MAP Kinase Kinase Kinase 1; C482576:MAP3K1 protein, human; D019703:Calcineurin
references.citation: J Virol. 2006 Sep;80(18):9279-87
references.pmid: 16940539
references.citation: Mol Cell Endocrinol. 2007 Feb;265-266:196-204
references.pmid: 17210223
references.citation: Oncogene. 2007 May 14;26(22):3240-53
references.pmid: 17496919
references.citation: J Leukoc Biol. 2002 Nov;72(5):847-55
references.pmid: 12429706
references.citation: Oncogene. 2002 Jun 27;21(28):4384-91
references.pmid: 12080469
references.citation: Mol Cell Biol. 2008 Mar;28(5):1644-56
references.pmid: 18086876
references.citation: EMBO J. 2007 Jun 20;26(12):2890-903
references.pmid: 17525731
references.citation: Proc Natl Acad Sci U S A. 2007 Mar 13;104(11):4700-5
references.pmid: 17360587
references.citation: J Biol Chem. 2003 Sep 26;278(39):37439-50
references.pmid: 12876282
references.citation: J Biol Chem. 2007 Jun 15;282(24):17649-57
references.pmid: 17452327
references.citation: J Biol Chem. 1996 Oct 18;271(42):25731-4
references.pmid: 8824197
references.citation: Cancer Cell. 2004 Nov;6(5):447-58
references.pmid: 15542429
references.citation: J Biol Chem. 1990 Mar 25;265(9):5267-72
references.pmid: 2156866
references.citation: EMBO J. 2005 Jul 6;24(13):2391-402
references.pmid: 15961999
references.citation: Cell. 2004 Oct 1;119(1):61-74
references.pmid: 15454081
references.citation: FEBS J. 2006 Jun;273(12):2730-48
references.pmid: 16817901
references.citation: PLoS One. 2006 Dec 20;1:e16
references.pmid: 17183642
references.citation: Nat Rev Mol Cell Biol. 2001 Aug;2(8):599-609
references.pmid: 11483993
references.citation: J Biol Chem. 1990 Dec 5;265(34):21128-33
references.pmid: 2250017
references.citation: J Biol Chem. 1998 Jul 17;273(29):18623-32
references.pmid: 9660836
references.citation: J Biol Chem. 1992 Nov 5;267(31):22506-11
references.pmid: 1331059
references.citation: J Biol Chem. 2006 Jul 21;281(29):20427-39
references.pmid: 16684769
references.citation: Gene Ther. 2008 Feb;15(3):191-202
references.pmid: 17972920
references.citation: J Biol Chem. 2004 Dec 17;279(51):52978-83
references.pmid: 15466468
references.citation: Oncogene. 2007 May 14;26(22):3159-71
references.pmid: 17496913
references.citation: Nucleic Acids Res. 2005 Mar 30;33(6):1859-73
references.pmid: 15800215
references.citation: Science. 2008 Mar 7;319(5868):1402-5
references.pmid: 18323454
references.citation: J Biol Chem. 2003 Jan 17;278(3):1403-6
references.pmid: 12456688
references.citation: Cell Metab. 2005 Nov;2(5):331-8
references.pmid: 16271533
references.citation: FEBS J. 2007 Jul;274(13):3202-9
references.pmid: 17565599
references.citation: Proc Natl Acad Sci U S A. 2001 Nov 20;98(24):13681-6
references.pmid: 11717429
references.citation: J Virol. 2006 Jul;80(14):7052-9
references.pmid: 16809310
references.citation: J Biol Chem. 1999 Jun 18;274(25):17402-5
references.pmid: 10364167
references.citation: J Biol Chem. 2001 May 11;276(19):16310-7
references.pmid: 11278389
references.citation: Nucleic Acids Res. 1998 Jan 15;26(2):486-9
references.pmid: 9421504
references.citation: FEBS J. 2007 Jul;274(13):3224-32
references.pmid: 17565603
references.citation: Mol Cell. 2003 Aug;12(2):413-23
references.pmid: 14536081
references.citation: Proc Natl Acad Sci U S A. 2002 Jun 11;99(12):7945-50
references.pmid: 12048245
references.citation: Mol Cell Biol. 2007 Jan;27(2):510-7
references.pmid: 17101801
references.citation: Nature. 2007 Sep 20;449(7160):366-9
references.pmid: 17805301
references.citation: Proc Natl Acad Sci U S A. 1998 Sep 1;95(18):10541-6
references.pmid: 9724739
references.citation: J Exp Med. 2008 Oct 27;205(11):2551-60
references.pmid: 18838543
references.citation: Proc Natl Acad Sci U S A. 2008 Jul 22;105(29):10161-6
references.pmid: 18626018
references.citation: Mol Cell. 2002 May;9(5):945-56
references.pmid: 12049732
references.citation: EMBO J. 2007 Jun 20;26(12):2880-9
references.pmid: 17476304
references.citation: Nature. 1994 Dec 22-29;372(6508):798-800
references.pmid: 7997270
references.citation: Nature. 2005 Oct 20;437(7062):1109-11
references.pmid: 16148943
references.citation: Annu Rev Biochem. 2006;75:137-63
references.pmid: 16756488
references.citation: Annu Rev Biochem. 1999;68:821-61
references.pmid: 10872467
references.citation: Cancer Res. 2005 Aug 15;65(16):7137-44
references.pmid: 16103063
references.citation: J Biol Chem. 1999 Apr 16;274(16):10916-22
references.pmid: 10196170
references.citation: Proc Natl Acad Sci U S A. 2000 May 9;97(10):5243-8
references.pmid: 10805784
references.citation: Proc Natl Acad Sci U S A. 2006 Sep 26;103(39):14379-84
references.pmid: 16980408
references.citation: Proc Natl Acad Sci U S A. 2007 Dec 18;104(51):20314-9
references.pmid: 18077367
references.citation: Curr Biol. 2004 Dec 14;14(23):2156-61
references.pmid: 15589160
references.citation: Proc Natl Acad Sci U S A. 2003 Oct 14;100(21):12147-52
references.pmid: 14506290
references.citation: Cell Signal. 2004 Nov;16(11):1211-27
references.pmid: 15337521
references.citation: Retrovirology. 2004 Jul 30;1:18
references.pmid: 15285791
references.citation: J Biol Chem. 2007 Sep 28;282(39):28335-28343
references.pmid: 17644518
references.citation: Proc Natl Acad Sci U S A. 1996 May 28;93(11):5291-5
references.pmid: 8643568
references.citation: Mol Cell Biol. 1998 Feb;18(2):967-77
references.pmid: 9447994
references.citation: FEBS Lett. 1998 Apr 10;426(1):93-6
references.pmid: 9598985
references.citation: Nat Cell Biol. 2006 Jul;8(7):717-24
references.pmid: 16767081
references.citation: Mol Cell Biol. 2000 Sep;20(17):6612-25
references.pmid: 10938135
references.citation: Immunology. 1989 Sep;68(1):31-6
references.pmid: 2478449
references.citation: Cell. 1991 Aug 23;66(4):807-15
references.pmid: 1715244
references.citation: Annu Rev Immunol. 2000;18:217-42
references.pmid: 10837058
references.citation: J Biol Chem. 1997 Oct 10;272(41):25816-23
references.pmid: 9325311
references.citation: Science. 2005 Dec 9;310(5754):1642-6
references.pmid: 16308421
references.citation: Proc Natl Acad Sci U S A. 2007 Jun 12;104(24):10175-80
references.pmid: 17548807