Selective mTORC1 Inhibitor Research Articles

Prostaglandin E2 induces activation of mTORC1 and mTORC2 in mast cells: selective utilization of mTORC2 for the regulation of chemotaxis and mediator release (151.6)

Abstract PGE2 is a potent modifier/regulator of multiple mast cell responses including FcϵRI-mediated degraulation, chemokine production, adhesion to basement membrane proteins, and chemotaxis. Nevertheless, how PGE2 regulates these diverse responses remains unclear. In mouse bone marrow-derived mast cells, we observed that PGE2 induced activation of mTORC1 (mTOR-raptor complex), as indicated by increased p70S6K and 4E-BP1 phosphorylation; and mTORC2 (mTOR-rictor complex), as indicated by increased phosphorylation of AKT at position Ser473. We thus investigated the roles of these signaling complexes in PGE2-mediated mast cell responses. Inhibition of mTORC1, through the use of the selective mTORC1 inhibitor rapamycin or by raptor-targeted shRNA, had minimal impact on PGE2-mediated chemotaxis or chemokine production. In contrast Torin, which inhibited both mTORC1 and mTORC2, and rictor-targeted shRNA, markedly reduced PGE2-mediated chemotaxis and this was associated with down-regulation of PGE2-induced cytoskeletal reorganization. Downregulation of mTORC2 furthermore attenuated PGE2-induced production of the chemokine CCL2, which was linked to a significant reduction in ROS production. Mast cell degranulation and adhesion were unaffected by down-regulation of either mTOR complex. Taken together, these data illustrate that mTOR2, is an important signal for chemotaxis and chemokine production from PGE2-activated mast cells.

320 POSTER Cellular characterization of OXA-01, a potent and selective dual mTORC1 and mTORC2 kinase inhibitor

320 POSTER Cellular characterization of OXA-01, a potent and selective dual mTORC1 and mTORC2 kinase inhibitor