Cross talk between the Akt and p38α pathways in macrophages downstream of Toll-like receptor signaling.

McGuire VA, Gray A, Monk CE, Santos SG, Lee K, Aubareda A, Crowe J, Ronkina N, Schwermann J, Batty IH, Leslie NR, Dean JL, O'Keefe SJ, Boothby M, Gaestel M, Arthur JS
Mol Cell Biol. 2013 33 (21): 4152-65

PMID: 23979601 · PMCID: PMC3811899 · DOI:10.1128/MCB.01691-12

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.

MeSH Terms (24)

Animals Cell Line Enzyme Activation Heat-Shock Proteins Imidazoles Intracellular Signaling Peptides and Proteins Lipopolysaccharides Macrophages Mice Mice, Inbred C57BL Mice, Transgenic Mitogen-Activated Protein Kinase 14 Neoplasm Proteins Phosphatidylinositol Phosphates Phosphorylation Protein-Serine-Threonine Kinases Protein Processing, Post-Translational Proto-Oncogene Proteins c-akt Pyridazines Pyridines Pyrimidines Receptor Cross-Talk Signal Transduction Toll-Like Receptors

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