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- Title
Enhancement of Mammalian Target of Rapamycin Complex-2 (TORC2) Kinase Activity by Fructose-2,6-Bisphosphate.
- Authors
Khan, Salmaan A.; Kim, Do-Hyung; Lange, Alex J.
- Abstract
Fructose-2,6-bisphosphate (F26BP) is a nutrient-derived signaling molecule that is made and broken down by the bifunctional enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase (BiF). In vivo elevation of F26BP via adenovirus-delivered kinase-dominant BiF is able to lower blood glucose levels without adverse effects on the lipid profile in type I and type II diabetic mouse models. The underlying mechanism by which F26BP achieves this involves the induction of glucokinase gene expression through the activation of Akt via Ser-473 phosphorylation. This was first observed in a streptozotocin-treated mouse that had no detectable circulating insulin, indicating insulinomimetic signaling by elevated F26BP. A recent report has identified the mTOR/rictor complex (TORC2) as an upstream kinase responsible for phosphorylating Akt at Ser-473. Therefore, we hypothesized that high F26BP signals downstream events by enhancing the ability of the TORC2 complex to phosphorylate Akt. In vitro kinase assays were conducted to demonstrate the effects of F26BP on TORC2 kinase activity. Our results indicate mTOR kinase activity is enhanced upon incubation with F26BP, implicating the mTOR/rictor complex in the F26BP signaling pathway. These findings define a mechanism by which high F26BP signals downstream targets to restore euglycemia in diabetic mouse models.
- Publication
Diabetes, 2007, Vol 56, pA516
- ISSN
0012-1797
- Publication type
Academic Journal