title: Cross talk between the Akt and p38α pathways in macrophages downstream of Toll-like receptor signaling.
abstract: The stimulation of Toll-like receptors (TLRs) on macrophages by pathogen-associated molecular patterns (PAMPs) results in the activation of intracellular signaling pathways that are required for initiating a host immune response. Both phosphatidylinositol 3-kinase (PI3K)-Akt and p38 mitogen-activated protein kinase (MAPK) signaling pathways are activated rapidly in response to TLR activation and are required to coordinate effective host responses to pathogen invasion. In this study, we analyzed the role of the p38-dependent kinases MK2/3 in the activation of Akt and show that lipopolysaccharide (LPS)-induced phosphorylation of Akt on Thr308 and Ser473 requires p38α and MK2/3. In cells treated with p38 inhibitors or an MK2/3 inhibitor, phosphorylation of Akt on Ser473 and Thr308 is reduced and Akt activity is inhibited. Furthermore, BMDMs deficient in MK2/3 display greatly reduced phosphorylation of Ser473 and Thr308 following TLR stimulation. However, MK2/3 do not directly phosphorylate Akt in macrophages but act upstream of PDK1 and mTORC2 to regulate Akt phosphorylation. Akt is recruited to phosphatidylinositol 3,4,5-trisphosphate (PIP3) in the membrane, where it is activated by PDK1 and mTORC2. Analysis of lipid levels in MK2/3-deficient bone marrow-derived macrophages (BMDMs) revealed a role for MK2/3 in regulating Akt activity by affecting availability of PIP3 at the membrane. These data describe a novel role for p38α-MK2/3 in regulating TLR-induced Akt activation in macrophages.
authors: Division of Cell Signalling and Immunology.
authors: Victoria A
authors: VA
authors: McGuire
authors: Alexander
authors: A
authors: Gray
authors: Claire E
authors: CE
authors: Monk
authors: Susana G
authors: SG
authors: Santos
authors: Keunwook
authors: K
authors: Lee
authors: Anna
authors: A
authors: Aubareda
authors: Jonathan
authors: J
authors: Crowe
authors: Natalia
authors: N
authors: Ronkina
authors: Jessica
authors: J
authors: Schwermann
authors: Ian H
authors: IH
authors: Batty
authors: Nick R
authors: NR
authors: Leslie
authors: Jonathan L E
authors: JL
authors: Dean
authors: Stephen J
authors: SJ
authors: O'Keefe
authors: Mark
authors: M
authors: Boothby
authors: Matthias
authors: M
authors: Gaestel
authors: J Simon C
authors: JS
authors: Arthur
mesh_terms: D000818:Animals; D002460:Cell Line; D004789:Enzyme Activation; D006360:Heat-Shock Proteins / Q000378:metabolism; D007093:Imidazoles / Q000494:pharmacology; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008070:Lipopolysaccharides / Q000494:pharmacology; D008264:Macrophages / Q000201:enzymology; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D048308:Mitogen-Activated Protein Kinase 14 / Q000037:antagonists & inhibitors / Q000378:metabolism*; D018832:Molecular Chaperones; D009363:Neoplasm Proteins / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D010766:Phosphorylation; D011499:Protein Processing, Post-Translational; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D011724:Pyridazines / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D011743:Pyrimidines / Q000494:pharmacology; D020239:Receptor Cross-Talk; D015398:Signal Transduction; D051193:Toll-Like Receptors / Q000819:agonists / Q000378:metabolism*; D000099190:MAP-Kinase-Activated Kinase 2
chemical_list: D006360:Heat-Shock Proteins; D007093:Imidazoles; D047908:Intracellular Signaling Peptides and Proteins; D008070:Lipopolysaccharides; D048308:Mitogen-Activated Protein Kinase 14; D018832:Molecular Chaperones; D009363:Neoplasm Proteins; D018129:Phosphatidylinositol Phosphates; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D011724:Pyridazines; D011725:Pyridines; D011743:Pyrimidines; D051193:Toll-Like Receptors; D000099190:MAP-Kinase-Activated Kinase 2; C486113:Hsbp1 protein, mouse; C055525:phosphatidylinositol 3-phosphate; C098416:MAP-kinase-activated kinase 3; C093642:SB 203580; C464966:VX-745
references: Mol Cell Biol. 2008 May;28(10):3258-72
references: 18347057
references: Mol Syst Biol. 2010 Jun 8;6:371
references: 20531401
references: Nat Immunol. 2012 Nov;13(11):1045-1054
references: 23023391
references: Genes Cancer. 2012 Jul;3(7-8):521-30
references: 23264852
references: Biochem J. 2009 Jun 12;421(1):29-42
references: 19402821
references: Anal Biochem. 2003 Feb 15;313(2):234-45
references: 12605860
references: Immunity. 2006 Nov;25(5):783-93
references: 17055754
references: EMBO J. 2004 May 19;23(10):2071-82
references: 15116068
references: Exp Hematol. 2003 Dec;31(12):1170-81
references: 14662322
references: Biochem J. 2004 Feb 15;378(Pt 1):257-68
references: 14611643
references: J Immunol. 2004 Apr 15;172(8):4851-7
references: 15067063
references: J Biol Chem. 2005 Dec 9;280(49):40406-16
references: 16221682
references: J Leukoc Biol. 2009 Jun;85(6):966-77
references: 19289601
references: Eur J Immunol. 2003 Feb;33(2):314-25
references: 12548562
references: Biochem J. 2012 Mar 15;442(3):465-81
references: 22364281
references: Dev Cell. 2006 Oct;11(4):583-9
references: 16962829
references: Mol Biol Cell. 2012 Aug;23(15):2982-92
references: 22675026
references: Biochem J. 2009 Sep 14;423(1):99-108
references: 19604150
references: J Biol Chem. 2007 Jul 27;282(30):21598-608
references: 17510053
references: Biochem J. 2007 Dec 15;408(3):297-315
references: 17850214
references: J Cell Biol. 2001 Oct 1;155(1):19-25
references: 11581283
references: Biochem J. 1998 Nov 15;336 ( Pt 1):241-6
references: 9806907
references: J Med Chem. 2008 Sep 25;51(18):5522-32
references: 18754654
references: Mol Cell Biol. 2008 Jan;28(1):61-70
references: 17967879
references: Science. 1997 Jan 31;275(5300):628-30
references: 9019819
references: Mol Immunol. 2006 Apr;43(10):1557-64
references: 16263172
references: EMBO J. 2013 Apr 3;32(7):1008-22
references: 23463102
references: Nat Immunol. 2003 Apr;4(4):313-9
references: 12660731
references: Cell. 2006 May 19;125(4):733-47
references: 16647110
references: Nat Rev Mol Cell Biol. 2006 Feb;7(2):120-30
references: 16421520
references: J Biol Chem. 2001 Jul 20;276(29):27462-9
references: 11313365
references: Nat Immunol. 2007 Nov;8(11):1227-35
references: 17906627
references: Nat Immunol. 2002 Sep;3(9):875-81
references: 12154357
references: EMBO J. 2002 Jul 15;21(14):3728-38
references: 12110585
references: Biochem J. 1998 Apr 1;331 ( Pt 1):299-308
references: 9512493
references: J Biol Chem. 2007 Mar 2;282(9):6232-41
references: 17202147
references: Trends Immunol. 2003 Jul;24(7):358-63
references: 12860525
references: Curr Opin Cell Biol. 1998 Apr;10(2):262-7
references: 9561851
references: EMBO J. 2003 Oct 15;22(20):5501-10
references: 14532122
references: Biochem J. 2007 Jan 1;401(1):29-38
references: 17040210
references: J Biol Chem. 2001 Feb 2;276(5):3517-23
references: 11042204
references: Cell. 2006 Jun 2;125(5):943-55
references: 16751103
references: Mol Cell Biol. 2005 Dec;25(23):10454-64
references: 16287858
references: Nat Immunol. 2000 Dec;1(6):533-40
references: 11101877
references: J Exp Med. 2012 Apr 9;209(4):713-28
references: 22473959
references: J Biol Chem. 2012 Sep 28;287(40):33215-26
references: 22859305
references: Biol Pharm Bull. 2007 Sep;30(9):1617-23
references: 17827709
references: Eur J Immunol. 2011 Jun;41(6):1733-41
references: 21469113
references: Am J Physiol Cell Physiol. 2004 Aug;287(2):C494-9
references: 15084475
references: Cell. 2007 Jun 29;129(7):1261-74
references: 17604717
references: Annu Rev Cell Dev Biol. 2001;17:615-75
references: 11687500
references: J Biol Chem. 2005 Feb 11;280(6):4029-36
references: 15546863
references: Cell Signal. 2004 Aug;16(8):951-7
references: 15157674
references: EMBO J. 1996 Dec 2;15(23):6541-51
references: 8978681
references: Mol Cell. 2006 Apr 21;22(2):159-68
references: 16603397
references: J Clin Oncol. 2011 Dec 10;29(35):4688-95
references: 22025163
references: Eur J Immunol. 2003 Mar;33(3):597-605
references: 12616480
references: J Immunol. 2008 Feb 15;180(4):2054-61
references: 18250410
references: J Biol Chem. 2006 Dec 1;281(48):37215-26
references: 17015449
references: Annu Rev Biochem. 1999;68:965-1014
references: 10872470
references: J Exp Med. 2003 May 5;197(9):1107-17
references: 12719479
references: Science. 2000 Feb 11;287(5455):1049-53
references: 10669418
references: J Immunol. 2004 Jul 1;173(1):360-6
references: 15210794
references: Front Biosci (Landmark Ed). 2011 Jan 01;16:517-30
references: 21196185
references: Science. 2005 Feb 18;307(5712):1098-101
references: 15718470
references: Mol Cell Biol. 2007 Jan;27(1):170-81
references: 17030606
references: J Pharmacol Exp Ther. 2010 Jun;333(3):797-807
references: 20237073
references: J Biol Chem. 2007 Nov 30;282(48):34663-71
references: 17855341
references: Nat Struct Mol Biol. 2004 Nov;11(11):1060-7
references: 15502848
references: Curr Opin Cell Biol. 1999 Apr;11(2):219-25
references: 10209156
references: Biochem J. 2007 Oct 15;407(2):255-66
references: 17672824
references: J Biol Chem. 2004 Sep 24;279(39):41189-96
references: 15262962
references: Curr Biol. 2000 Apr 20;10(8):439-48
references: 10801415
references: Oncogene. 2008 Oct 27;27(50):6473-88
references: 18955974
references: PLoS One. 2013;8(3):e60086
references: 23533666
references: Am J Physiol Endocrinol Metab. 2005 Aug;289(2):E187-96
references: 16014356