Metformin, independent of AMPK, inhibits mTORC1 in a rag GTPase-dependent manner.
Dysfunctional mTORC1 signaling is associated with a number of human pathologies owing to its central role in controlling cell growth, proliferation, and metabolism. Regulation of mTORC1 is achieved by the integration of multiple inputs, including those of mitogens, nutrients, and energy. It is thought that agents that increase the cellular AMP/ATP ratio, such as the antidiabetic biguanides metformin and phenformin, inhibit mTORC1 through AMPK activation of TSC1/2-dependent or -independent mechanisms. Unexpectedly, we found that biguanides inhibit mTORC1 signaling, not only in the absence of TSC1/2 but also in the absence of AMPK. Consistent with these observations, in two distinct preclinical models of cancer and diabetes, metformin acts to suppress mTORC1 signaling in an AMPK-independent manner. We found that the ability of biguanides to inhibit mTORC1 activation and signaling is, instead, dependent on the Rag GTPases.
Kalender
Adem
A
Department of Cancer and Cell Biology, Metabolic Diseases Institute, University of Cincinnati, 2180 E. Galbraith Road, Cincinnati, OH 45237, USA.
Selvaraj
Anand
A
Kim
So Young
SY
Gulati
Pawan
P
Brûlé
Sophie
S
Viollet
Benoit
B
Kemp
Bruce E
BE
Bardeesy
Nabeel
N
Dennis
Patrick
P
Schlager
John J
JJ
Marette
André
A
Kozma
Sara C
SC
Thomas
George
G
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D004330:Drosophila / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D007004:Hypoglycemic Agents / Q000494:pharmacology*; D000076222:Mechanistic Target of Rapamycin Complex 1; D008687:Metformin / Q000494:pharmacology*; D051379:Mice; D008969:Molecular Sequence Data; D020559:Monomeric GTP-Binding Proteins / Q000378:metabolism*; D046912:Multiprotein Complexes; D010629:Phenformin / Q000494:pharmacology; D011506:Proteins; D016415:Sequence Alignment; D015398:Signal Transduction; D058570:TOR Serine-Threonine Kinases; D014157:Transcription Factors / Q000037:antagonists & inhibitors* / Q000378:metabolism; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D007004:Hypoglycemic Agents; D046912:Multiprotein Complexes; D011506:Proteins; C000624650:TSC1 protein, human; D014157:Transcription Factors; C000624651:Tsc1 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D008687:Metformin; D010629:Phenformin; D000076222:Mechanistic Target of Rapamycin Complex 1; D058570:TOR Serine-Threonine Kinases; D055372:AMP-Activated Protein Kinases; D020559:Monomeric GTP-Binding Proteins; D005947:Glucose
Mol Cell. 2008 Apr 25;30(2):214-26
18439900
Nat Rev Cancer. 2009 Aug;9(8):563-75
19629071
Mol Cancer Ther. 2007 Feb;6(2):732-41
17308069
Science. 2007 Nov 9;318(5852):977-80
17991864
FEBS Lett. 2008 Jan 9;582(1):81-9
18022388
Science. 2001 Nov 2;294(5544):1102-5
11691993
Diabetes Care. 2006 Aug;29(8):1990-1
16873829
J Biol Chem. 2006 Sep 15;281(37):27643-52
16847060
Biochem J. 2002 Oct 1;367(Pt 1):179-86
12093363
J Biol Chem. 2005 Nov 25;280(47):39505-9
16183647
J Clin Invest. 2001 Oct;108(8):1167-74
11602624
Nat Cell Biol. 2008 Aug;10(8):935-45
18604198
Curr Biol. 2005 Apr 26;15(8):702-13
15854902
Nat Cell Biol. 2007 Mar;9(3):316-23
17277771
Physiol Rev. 2009 Jul;89(3):1025-78
19584320
Biochem J. 1992 Dec 1;288 ( Pt 2):433-8
1463447
Mol Cell Biol. 2006 Jan;26(1):63-76
16354680
J Biol Chem. 2001 Dec 14;276(50):46912-6
11598104
Nat Cell Biol. 2002 Sep;4(9):699-704
12172555
Proc Natl Acad Sci U S A. 2007 Aug 28;104(35):14056-61
17709744
Oncogene. 2006 Aug 7;25(34):4777-86
16892090
EMBO J. 2005 May 18;24(10):1810-20
15889149
J Biol Chem. 1957 Feb;224(2):963-9
13405925
J Cell Biol. 2004 Jul 19;166(2):213-23
15249583
Science. 2008 Jun 13;320(5882):1496-501
18497260
Sci STKE. 2006 Aug 01;2006(346):re7
16885148
Proc Natl Acad Sci U S A. 2005 Oct 4;102(40):14238-43
16176982
Oncogene. 2005 May 26;24(23):3830-5
15750626
Mol Cell. 2007 Mar 23;25(6):903-15
17386266
Cell. 2002 Jul 26;110(2):163-75
12150925
Clin Cancer Res. 2003 Aug 15;9(9):3469-75
12960139
Diabetes Care. 2009 Sep;32(9):1620-5
19564453
Cancer Cell. 2003 Aug;4(2):147-58
12957289
Cell Metab. 2008 May;7(5):456-65
18460336
Cancer Cell. 2004 Jul;6(1):7-10
15261137
Mol Cell. 2003 Jun;11(6):1457-66
12820960
Cell. 2003 Nov 26;115(5):577-90
14651849
Cancer Res. 2007 Nov 15;67(22):10804-12
18006825
Biochem J. 1997 Jul 15;325 ( Pt 2):487-93
9230132
Cell. 2007 Jun 29;129(7):1261-74
17604717
Mol Cell Biol. 2005 Jul;25(14):5834-45
15988001
Cancer Treat Rep. 1983 Oct;67(10):901-4
6354438
Nat Rev Cancer. 2006 Sep;6(9):729-34
16915295
Diabetes. 2006 Apr;55(4):865-74
16567505
J Biol Chem. 2005 May 13;280(19):18717-27
15772076
J Cell Biol. 2002 Oct 28;159(2):217-24
12403809
J Biol Chem. 2005 Sep 23;280(38):33076-82
16049009
N Engl J Med. 1996 Feb 29;334(9):574-9
8569826
Second Messengers Phosphoproteins. 1992;14(1-2):55-63
1403850
Cell Metab. 2006 Jun;3(6):393-402
16753575
Mol Cell Biol. 2006 Jul;26(14):5336-47
16809770
Diabetes. 2008 Apr;57(4):945-57
18174523
Genes Dev. 2002 Oct 15;16(20):2627-32
12381661
Nature. 2004 Sep 9;431(7005):200-5
15306821
Science. 2005 Feb 18;307(5712):1098-101
15718470
J Cell Physiol. 2009 Jan;218(1):167-74
18781596
Trends Mol Med. 2007 Jun;13(6):252-9
17452018
Semin Cancer Biol. 2009 Feb;19(1):17-24
19101634
Genes Dev. 2008 Jan 15;22(2):239-51
18198340
Protein Sci. 2004 Jan;13(1):155-65
14691231
Science. 2005 Dec 9;310(5754):1642-6
16308421
Cell. 2006 Feb 10;124(3):471-84
16469695