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

Victoria A. McGuire, Alexander Gray, Claire E. Monk, Susana G. Santos, Keunwook Lee, Anna Aubareda, Jonathan Crowe, Natalia Ronkina, Jessica Schwermann, Ian H. Batty, Nicholas R. Leslie, Jonathan L. E. Dean, Stephen J. O'Keefe, Mark Boothby, Matthias Gaestel, J. Simon C. Arthur

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    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 p38a 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 p38a-MK2/3 in regulating TLR-induced Akt activation in macrophages.
    Original languageEnglish
    Pages (from-to)4152-4165
    Number of pages14
    JournalMolecular and Cellular Biology
    Volume33
    Issue number21
    DOIs
    Publication statusPublished - 2013

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  • Cite this

    McGuire, V. A., Gray, A., Monk, C. E., Santos, S. G., Lee, K., Aubareda, A., Crowe, J., Ronkina, N., Schwermann, J., Batty, I. H., Leslie, N. R., Dean, J. L. E., O'Keefe, S. J., Boothby, M., Gaestel, M., & Arthur, J. S. C. (2013). Cross talk between the Akt and p38α pathways in macrophages downstream of toll-like receptor signaling. Molecular and Cellular Biology, 33(21), 4152-4165. https://doi.org/10.1128/MCB.01691-12