Search for directed genic interactions:  

MTOR SYT1 (1 - 1 of 1)
PMID: 21422248
Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-ß-signaling pathways regulates the innate inflammatory response.
... mTORC1 inhibition increased the ... NF-?B p65 associated ...   (details)

MTOR SYT1

Type:  negative regulation
Is this interaction correct?
Yes
No

Comments

Cause:  mTORC1   (MLST8   RPTOR   MTOR )

PMID: 21422248

Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-ß-signaling pathways regulates the innate inflammatory response.
Source

Journal of immunology (Baltimore, Md. : 1950; 5/1/2011)

Abstract

Convergence of the mammalian target of rapamycin complex 1- and glycogen synthase kinase 3-ß-signaling pathways regulates the innate inflammatory response. The PI3K pathway and its regulation of mammalian target of rapamycin complex 1 (mTORC1) and glycogen synthase kinase 3 (GSK3) play pivotal roles in controlling inflammation. In this article, we show that mTORC1 and GSK3-ß converge and that the capacity of mTORC1 to affect the inflammatory response is due to the inactivation of GSK3-ß. Inhibition of mTORC1 attenuated GSK3 phosphorylation and increased its kinase activity. Immunoprecipitation and in vitro kinase assays demonstrated that GSK3-ß associated with a downstream target of mTORC1, p85S6K, and phosphorylated GSK3-ß. Inhibition of S6K1 abrogated the phosphorylation of GSK3-ß while increasing and decreasing the levels of IL-12 and IL-10, respectively, in LPS-stimulated monocytes. In contrast, the direct inhibition of GSK3 attenuated the capacity of S6K1 inhibition to influence the levels of IL-10 and IL-12 produced by LPS-stimulated cells. At the transcriptional level, mTORC1 inhibition reduced the DNA binding of CREB and this effect was reversed by GSK3 inhibition. As a result, mTORC1 inhibition increased the levels of NF-?B p65 associated with CREB-binding protein. Inhibition of NF-?B p65 attenuated rapamycin's ability to influence the levels of pro- or anti-inflammatory cytokine production in monocytes stimulated with LPS. These studies identify the molecular mechanism by which mTORC1 affects GSK3 and show that mTORC1 inhibition regulates pro- and anti-inflammatory cytokine production via its capacity to inactivate GSK3.