|Burrin, Douglas - Doug|
Submitted to: Endocrine Society Meeting
Publication Type: Abstract Only
Publication Acceptance Date: 6/3/2007
Publication Date: 6/3/2007
Citation: Guan, X., Li, X., Li, D., Wang, Y., Qiao, S., Burrin, D., Chang, B., Chan, L. 2007. Glucagon-like peptide-2 (GLP-2) activates the mTOR signaling through a PI3-kinase-Akt-dependent pathway [abstract]. "ENDO 07", 89th Annual Meeting of the Endocrine Society, Juen 2-5, 2007, Toronto, Canada. Paper No. P2-595. Interpretive Summary:
Technical Abstract: GLP-2 is a nutrient-responsive enterotrophic neuropeptide that exerts diverse actions in the gastrointestinal tract including enhancing mucosal cell survival and proliferation, inducing mucosal blood flow and anabolic metabolism, and suppressing gastric motility and secretion. GLP-2-stimulated mucosal growth occurred in vivo with an increased rate of protein synthesis in the neonatal intestine, which was associated with up-regulated phosphorylation of Akt kinase and endothelial nitric oxide synthase (eNOS). GLP-2 receptor (GLP-2R, a G protein-coupled receptor) is co-localized with eNOS in enteric neurons. Increasing evidence indicates that protein translation and cell proliferation are mainly controlled by the mammalian target of rapamycin (mTOR) signaling pathway. Thus, we hypothesized that GLP-2R activation intracellularly stimulated the mTOR signaling through a phosphatidylinositol 3 (PI3)-kinase-Akt pathway. Our aim was to establish whether GLP-2R activation induces mTOR phosphorylation through the PI3-Akt-dependent pathway. The HEK 293 cells transfected transiently with full-length cDNAs of human GLP-2R and eNOS were treated with human GLP-2 (20 nM) with/without pre-treatment of a PI3-kinase inhibitor (LY294002, 50 mM). Results show that  GLP-2 stimulated Akt phosphorylation at Ser473 (+42%) and Thr308 (+42%), which was suppressed by the inhibitor by 60% and 30%, respectively.  GLP-2 stimulated eNOS phosphorylation at Ser1177 (+21%) and Ser633 (+55%), which was suppressed by the inhibitor by 42% and 10%, respectively.  GLP-2 stimulated mTOR phosphorylation at Ser2448 (+25%), thus activating p70S6 kinase and inactivating the elF4E inhibitor (4E-BP1) by inducing phosphorylation of p70S6 kinase at Thr389 (+28%) and hyperphosphorylation of 4E-BP1 at Thr37/46 (+20%), which was suppressed by the inhibitor by 35% and 20%, respectively. We concluded that GLP-2R activation stimulated the mTOR signaling pathway and was partially mediated by the PI3-kinase-Akt signaling pathway. The study suggests that GLP-2 stimulate the mTOR-controlled protein synthesis in GLP-2R-expressed cells, which indirectly mediates GLP-2-stimulated anabolic and tropic actions in the gut.