title: Identification of IRS-1 Ser-1101 as a target of S6K1 in nutrient- and obesity-induced insulin resistance.
abstract: S6K1 has emerged as a critical signaling component in the development of insulin resistance through phosphorylation and inhibition of IRS-1 function. This effect can be triggered directly by nutrients such as amino acids or by insulin through a homeostatic negative-feedback loop. However, the role of S6K1 in mediating IRS-1 phosphorylation in a physiological setting of nutrient overload is unresolved. Here we show that S6K1 directly phosphorylates IRS-1 Ser-1101 in vitro in the C-terminal domain of the protein and that mutation of this site largely blocks the ability of amino acids to suppress IRS-1 tyrosine and Akt phosphorylation. Consistent with this finding, phosphorylation of IRS-1 Ser-1101 is increased in the liver of obese db/db and wild-type, but not S6K1(-/-), mice maintained on a high-fat diet and is blocked by siRNA knockdown of S6K1 protein. Finally, infusion of amino acids in humans leads to the concomitant activation of S6K1, phosphorylation of IRS-1 Ser-1101, a reduction in IRS-1 function, and insulin resistance in skeletal muscle. These findings indicate that nutrient- and hormonal-dependent activation of S6K1 causes insulin resistance in mice and humans, in part, by mediating IRS-1 Ser-1101 phosphorylation.
authors: Department of Anatomy and Physiology, Laval University Hospital Research Center, Ste-Foy, QC, Canada G1V 4G2.
authors: Frédéric
authors: F
authors: Tremblay
authors: Sophie
authors: S
authors: Brûlé
authors: Sung
authors: S
authors: Hee Um
authors: Yu
authors: Y
authors: Li
authors: Kohei
authors: K
authors: Masuda
authors: Michael
authors: M
authors: Roden
authors: Xiao Jian
authors: XJ
authors: Sun
authors: Michael
authors: M
authors: Krebs
authors: Roberto D
authors: RD
authors: Polakiewicz
authors: George
authors: G
authors: Thomas
authors: André
authors: A
authors: Marette
mesh_terms: D000818:Animals; D006801:Humans; D055504:Insulin Receptor Substrate Proteins; D007333:Insulin Resistance / Q000502:physiology*; D051379:Mice; D009752:Nutritional Status; D009765:Obesity / Q000503:physiopathology*; D010750:Phosphoproteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D010766:Phosphorylation; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D012694:Serine; D020123:Sirolimus / Q000494:pharmacology
chemical_list: C526292:IRS1 protein, human; D055504:Insulin Receptor Substrate Proteins; C526295:Irs1 protein, mouse; D010750:Phosphoproteins; D012333:RNA, Messenger; D034741:RNA, Small Interfering; D012694:Serine; D020123:Sirolimus
references: Am J Physiol. 1986 Nov;251(5 Pt 1):E576-83
references: 3535532
references: Annu Rev Biochem. 1975;44:933-55
references: 1094924
references: Diabetes. 1991 Nov;40(11):1397-403
references: 1936601
references: J Biol Chem. 1992 Feb 15;267(5):3074-8
references: 1737763
references: J Biol Chem. 1997 Dec 12;272(50):31400-6
references: 9395471
references: EMBO J. 1998 Nov 16;17(22):6649-59
references: 9822608
references: J Clin Invest. 1999 Apr;103(7):931-43
references: 10194465
references: J Biol Chem. 1999 Apr 9;274(15):10625-32
references: 10187859
references: N Engl J Med. 1999 Jul 22;341(4):248-57
references: 10413738
references: Trends Biochem Sci. 2005 Jan;30(1):35-42
references: 15653324
references: Endocrinology. 2005 Mar;146(3):1328-37
references: 15576463
references: Endocrinology. 2005 Mar;146(3):1473-81
references: 15604215
references: Cell Cycle. 2005 Jan;4(1):46-51
references: 15611656
references: Diabetes. 2005 Sep;54(9):2674-84
references: 16123357
references: Mol Cell Biol. 2006 Jan;26(1):63-76
references: 16354680
references: Cell Metab. 2006 Jun;3(6):393-402
references: 16753575
references: Mol Cell Biol. 2006 Sep;26(17):6425-34
references: 16914728
references: Nat Cell Biol. 2002 Mar;4(3):251-5
references: 11862217
references: Genes Dev. 2002 Oct 15;16(20):2627-32
references: 12381661
references: Am J Physiol Endocrinol Metab. 2002 Sep;283(3):E413-22
references: 12169433
references: J Biol Chem. 2000 Mar 24;275(12):9047-54
references: 10722755
references: J Biol Chem. 2002 Dec 13;277(50):48115-21
references: 12351658
references: Mol Endocrinol. 2000 Jun;14(6):783-94
references: 10847581
references: Am J Physiol Endocrinol Metab. 2000 Oct;279(4):E715-29
references: 11001751
references: Nature. 2000 Dec 21-28;408(6815):994-7
references: 11140689
references: Proc Natl Acad Sci U S A. 2001 Apr 10;98(8):4640-5
references: 11287630
references: J Biol Chem. 2001 Apr 27;276(17):14459-65
references: 11278339
references: J Biol Chem. 2001 Feb 2;276(5):3543-9
references: 11063744
references: Mol Cell Biol. 2001 Aug;21(15):5050-62
references: 11438661
references: J Biol Chem. 2001 Oct 12;276(41):38052-60
references: 11498541
references: Trends Cell Biol. 2001 Nov;11(11):437-41
references: 11684411
references: Diabetes. 2002 Mar;51(3):599-605
references: 11872656
references: Curr Top Microbiol Immunol. 2004;279:283-98
references: 14560964
references: Diabetologia. 2003 Nov;46(11):1532-42
references: 14579029
references: Biochem Biophys Res Commun. 2004 Apr 2;316(2):533-9
references: 15020250
references: Curr Med Chem. 2004 Apr;11(7):901-8
references: 15078172
references: Diabetes. 2004 Jul;53(7):1633-42
references: 15220184
references: J Cell Biol. 2004 Jul 19;166(2):213-23
references: 15249583
references: Genes Dev. 2004 Aug 15;18(16):1926-45
references: 15314020
references: Nature. 2004 Sep 9;431(7005):200-5
references: 15306821
references: Curr Biol. 2004 Sep 21;14(18):1650-6
references: 15380067
references: Int J Obes Relat Metab Disord. 1997 Aug;21(8):698-703
references: 15481771
references: J Biol Chem. 2004 Oct 29;279(44):45304-7
references: 15364919
references: N Engl J Med. 1969 Oct 9;281(15):811-6
references: 5809519
references: Diabetes. 1991 Feb;40(2):280-9
references: 1991575