Gene interactions and pathways from curated databases and text-mining
Proc Natl Acad Sci U S A 2007, PMID: 18077353

FoxO transcription factors activate Akt and attenuate insulin signaling in heart by inhibiting protein phosphatases.

Ni, Yan G; Wang, Na; Cao, Dian J; Sachan, Nita; Morris, David J; Gerard, Robert D; Kuro-O, Makoto; Rothermel, Beverly A; Hill, Joseph A

Insulin resistance and metabolic syndrome are rapidly expanding public health problems. Acting through the PI3K/Akt pathway, insulin and insulin-like growth factor-1 (IGF-1) inactivate FoxO transcription factors, a class of highly conserved proteins important in numerous physiological functions. However, even as FoxO is a downstream target of insulin, FoxO factors also control upstream signaling elements governing insulin sensitivity and glucose metabolism. Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity. FoxO-activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition. We reported previously that FoxO factors attenuate cardiomyocyte calcineurin (PP2B) activity. We now show that calcineurin forms a complex with Akt and inhibition of calcineurin enhances Akt phosphorylation. In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions. Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO-dependent increases in Akt phosphorylation and kinase activity. Resveratrol, an activator of Sirt1, increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart. Importantly, FoxO-mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin-triggered glucose uptake. Also, inactivation of the gene coding for FoxO3 enhances insulin-dependent Akt phosphorylation. Taken together, this study demonstrates that changes in FoxO activity have a dose-responsive repressive effect on insulin signaling in cardiomyocytes through inhibition of protein phosphatases, which leads to altered Akt activation, reduced insulin sensitivity, and impaired glucose metabolism.

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

Text Mining Data

Akt → FoxO1: " Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity "

Akt → FoxO3: " Here, we report that sustained activation of either FoxO1 or FoxO3 in cardiac myocytes increases basal levels of Akt phosphorylation and kinase activity "

Akt → FoxO: " FoxO activated Akt directly interacts with and phosphorylates FoxO, providing feedback inhibition "

Akt-PP2A ⊣ FoxO: " In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions "

Akt-PP2A ⊣ FoxO: " In addition, FoxO activity suppresses protein phosphatase 2A (PP2A) and disrupts Akt-PP2A and Akt-calcineurin interactions "

Akt ⊣ Akt-PP2A/B: " Repression of Akt-PP2A/B interactions and phosphatase activities contributes , at least in part, to FoxO dependent increases in Akt phosphorylation and kinase activity "

Akt → FoxO: " Repression of Akt-PP2A/B interactions and phosphatase activities contributes, at least in part, to FoxO dependent increases in Akt phosphorylation and kinase activity "

FoxO1 → Sirt1: " Resveratrol, an activator of Sirt1 , increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart "

Akt → Sirt1: " Resveratrol, an activator of Sirt1 , increases the transcriptional activity of FoxO1 and triggers Akt phosphorylation in heart "

Glut4 ⊣ FoxO: " Importantly, FoxO mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4 , and decreased insulin triggered glucose uptake "

Glut4 ⊣ Akt: " Importantly, FoxO mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4 , and decreased insulin triggered glucose uptake "

Glut4 ⊣ insulin: " Importantly, FoxO mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4 , and decreased insulin triggered glucose uptake "

Akt → FoxO: " Importantly, FoxO mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin triggered glucose uptake "

insulin → FoxO: " Importantly, FoxO mediated increases in Akt activity diminish insulin signaling, as manifested by reduced Akt phosphorylation, reduced membrane translocation of Glut4, and decreased insulin triggered glucose uptake "

Akt → insulin: " Also, inactivation of the gene coding for FoxO3 enhances insulin dependent Akt phosphorylation "

Manually curated Databases

No curated data.