Gene interactions and pathways from curated databases and text-mining
J Biol Chem 2011, PMID: 22045807

Mammalian target of rapamycin complex 2 (mTORC2) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1.

Brown, Jonathan; Wang, Huizhi; Suttles, Jill; Graves, Dana T; Martin, Michael

Activation of the PI3K pathway plays a pivotal role in regulating the inflammatory response. The loss of mTORC2 has been shown to abrogate the activation of Akt, a critical downstream component of PI3K signaling. However, the biological importance of mTORC2 in innate immunity is currently unknown. Here we demonstrate that rictor, a key component of mTORC2, plays a critical role in controlling the innate inflammatory response via its ability to regulate FoxO1. Upon LPS stimulation, both rictor-deficient mouse embryonic fibroblasts (MEFs) and rictor knockdown dendritic cells exhibited a hyperinflammatory phenotype. The hyperinflammatory phenotype was due to a defective Akt signaling axis, because both rictor-deficient MEFs and rictor knockdown dendritic cells exhibited attenuated Akt phosphorylation and kinase activity. Analysis of downstream Akt targets revealed that phosphorylation of FoxO1 was impaired in rictor-deficient cells, resulting in elevated nuclear FoxO1 levels and diminished nuclear export of FoxO1 upon LPS stimulation. Knockdown of FoxO1 attenuated the hyperinflammatory phenotype exhibited by rictor-deficient MEFs. Moreover, FoxO1 deletion in dendritic cells attenuated the capacity of LPS to induce inflammatory cytokine expression. These findings identify a novel signaling pathway by which mTORC2 regulates the TLR-mediated inflammatory response through its ability to regulate FoxO1.

Diseases/Pathways annotated by Medline MESH: Inflammation
Document information provided by NCBI PubMed

Text Mining Data

Toll-like receptor 4-mediated → Mammalian target of rapamycin: " Mammalian target of rapamycin complex 2 ( mTORC2 ) negatively regulates Toll-like receptor 4-mediated inflammatory response via FoxO1 "

Manually curated Databases

No curated data.