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Prostaglandin E2 activates and utilizes mTORC2 as a central signaling locus for the regulation of mast cell chemotaxis and mediator release.
- Source :
-
The Journal of biological chemistry [J Biol Chem] 2011 Jan 07; Vol. 286 (1), pp. 391-402. Date of Electronic Publication: 2010 Oct 27. - Publication Year :
- 2011
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Abstract
- Prostaglandin (PG) E(2), a potent mediator produced in inflamed tissues, can substantially influence mast cell responses including adhesion to basement membrane proteins, chemotaxis, and chemokine production. However, the signaling pathways by which PGE(2) induces mast cell chemotaxis and chemokine production remains undefined. In this study, we identified the downstream target of phosphatidylinositol 3-kinase, mammalian target of rapamycin (mTOR), as a key regulator of these responses. In mouse bone marrow-derived mast cells, PGE(2) was found to induce activation of mTORC1 (mTOR complexed to raptor) as indicated by increased p70S6K and 4E-BP1 phosphorylation, and activation of mTORC2 (mTOR complexed to rictor), as indicated by increased phosphorylation of AKT at position Ser(473). Selective inhibition of the mTORC1 cascade by rapamycin or by the use of raptor-targeted shRNA failed to decrease PGE(2)-mediated chemotaxis or chemokine generation. However, inhibition of the mTORC2 cascade through the dual mTORC1/mTORC2 inhibitor Torin, or through rictor-targeted shRNA, resulted in a significant attenuation in PGE(2)-mediated chemotaxis, which was associated with a comparable decrease in actin polymerization. Furthermore, mTORC2 down-regulation decreased PGE(2)-induced production of the chemokine monocyte chemoattractant protein-1 (CCL2), which was linked to a significant reduction in ROS production. These findings are consistent with the conclusion that activation of mTORC2, downstream of PI3K, represents a critical signaling locus for chemotaxis and chemokine release from PGE(2)-activated mast cells.
- Subjects :
- Actins chemistry
Animals
Bone Marrow Cells cytology
Chemokine CCL2 biosynthesis
Gene Knockdown Techniques
Mast Cells drug effects
Mechanistic Target of Rapamycin Complex 1
Mice
Mitogen-Activated Protein Kinases metabolism
Multiprotein Complexes
Phosphatidylinositol 3-Kinases metabolism
Prostaglandin D2 biosynthesis
Protein Multimerization drug effects
Protein Structure, Quaternary
Proteins metabolism
Receptors, Prostaglandin E, EP3 Subtype metabolism
TOR Serine-Threonine Kinases
Trans-Activators antagonists & inhibitors
Trans-Activators deficiency
Trans-Activators genetics
Transcription Factors antagonists & inhibitors
Transcription Factors deficiency
Transcription Factors genetics
Chemokines metabolism
Chemotaxis drug effects
Dinoprostone pharmacology
Mast Cells cytology
Mast Cells metabolism
Signal Transduction drug effects
Trans-Activators metabolism
Transcription Factors metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1083-351X
- Volume :
- 286
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- The Journal of biological chemistry
- Publication Type :
- Academic Journal
- Accession number :
- 20980255
- Full Text :
- https://doi.org/10.1074/jbc.M110.164772