PMID- 23979601
OWN - NLM
STAT- MEDLINE
DCOM- 20131209
LR  - 20220129
IS  - 1098-5549 (Electronic)
IS  - 0270-7306 (Print)
IS  - 0270-7306 (Linking)
VI  - 33
IP  - 21
DP  - 2013 Nov
TI  - Cross talk between the Akt and p38alpha pathways in macrophages downstream of 
      Toll-like receptor signaling.
PG  - 4152-65
LID - 10.1128/MCB.01691-12 [doi]
AB  - 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 p38alpha 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 p38alpha-MK2/3 in regulating TLR-induced Akt 
      activation in macrophages.
FAU - McGuire, Victoria A
AU  - McGuire VA
AD  - Division of Cell Signalling and Immunology.
FAU - Gray, Alexander
AU  - Gray A
FAU - Monk, Claire E
AU  - Monk CE
FAU - Santos, Susana G
AU  - Santos SG
FAU - Lee, Keunwook
AU  - Lee K
FAU - Aubareda, Anna
AU  - Aubareda A
FAU - Crowe, Jonathan
AU  - Crowe J
FAU - Ronkina, Natalia
AU  - Ronkina N
FAU - Schwermann, Jessica
AU  - Schwermann J
FAU - Batty, Ian H
AU  - Batty IH
FAU - Leslie, Nick R
AU  - Leslie NR
FAU - Dean, Jonathan L E
AU  - Dean JL
FAU - O'Keefe, Stephen J
AU  - O'Keefe SJ
FAU - Boothby, Mark
AU  - Boothby M
FAU - Gaestel, Matthias
AU  - Gaestel M
FAU - Arthur, J Simon C
AU  - Arthur JS
LA  - eng
GR  - G0801865/MRC_/Medical Research Council/United Kingdom
GR  - R01 HL106812/HL/NHLBI NIH HHS/United States
GR  - ARC_/Arthritis Research UK/United Kingdom
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20130826
PL  - United States
TA  - Mol Cell Biol
JT  - Molecular and cellular biology
JID - 8109087
RN  - 0 (Heat-Shock Proteins)
RN  - 0 (Hsbp1 protein, mouse)
RN  - 0 (Imidazoles)
RN  - 0 (Intracellular Signaling Peptides and Proteins)
RN  - 0 (Lipopolysaccharides)
RN  - 0 (Molecular Chaperones)
RN  - 0 (Neoplasm Proteins)
RN  - 0 (Phosphatidylinositol Phosphates)
RN  - 0 (Pyridazines)
RN  - 0 (Pyridines)
RN  - 0 (Pyrimidines)
RN  - 0 (Toll-Like Receptors)
RN  - 0 (phosphatidylinositol 3-phosphate)
RN  - EC 2.7.1.- (MAP-kinase-activated kinase 2)
RN  - EC 2.7.1.- (MAP-kinase-activated kinase 3)
RN  - EC 2.7.11.1 (Protein Serine-Threonine Kinases)
RN  - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt)
RN  - EC 2.7.11.24 (Mitogen-Activated Protein Kinase 14)
RN  - OU13V1EYWQ (SB 203580)
RN  - TYL52QM320 (VX-745)
SB  - IM
MH  - Animals
MH  - Cell Line
MH  - Enzyme Activation
MH  - Heat-Shock Proteins/metabolism
MH  - Imidazoles/pharmacology
MH  - Intracellular Signaling Peptides and Proteins/*metabolism
MH  - Lipopolysaccharides/pharmacology
MH  - Macrophages/enzymology
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Transgenic
MH  - Mitogen-Activated Protein Kinase 14/antagonists & inhibitors/*metabolism
MH  - Molecular Chaperones
MH  - Neoplasm Proteins/metabolism
MH  - Phosphatidylinositol Phosphates/metabolism
MH  - Phosphorylation
MH  - Protein Processing, Post-Translational
MH  - Protein Serine-Threonine Kinases/*metabolism
MH  - Proto-Oncogene Proteins c-akt/*metabolism
MH  - Pyridazines/pharmacology
MH  - Pyridines/pharmacology
MH  - Pyrimidines/pharmacology
MH  - Receptor Cross-Talk
MH  - Signal Transduction
MH  - Toll-Like Receptors/agonists/*metabolism
PMC - PMC3811899
EDAT- 2013/08/28 06:00
MHDA- 2013/12/16 06:00
PMCR- 2014/05/01
CRDT- 2013/08/28 06:00
PHST- 2013/08/28 06:00 [entrez]
PHST- 2013/08/28 06:00 [pubmed]
PHST- 2013/12/16 06:00 [medline]
PHST- 2014/05/01 00:00 [pmc-release]
AID - MCB.01691-12 [pii]
AID - 01691-12 [pii]
AID - 10.1128/MCB.01691-12 [doi]
PST - ppublish
SO  - Mol Cell Biol. 2013 Nov;33(21):4152-65. doi: 10.1128/MCB.01691-12. Epub 2013 Aug 
      26.