| First Author | Jiao P | Year | 2012 |
| Journal | PLoS One | Volume | 7 |
| Issue | 7 | Pages | e41168 |
| PubMed ID | 22848439 | Mgi Jnum | J:189706 |
| Mgi Id | MGI:5446870 | Doi | 10.1371/journal.pone.0041168 |
| Citation | Jiao P, et al. (2012) Mapping MKP-3/FOXO1 interaction and evaluating the effect on gluconeogenesis. PLoS One 7(7):e41168 |
| abstractText | BACKGROUND: MAP kinase phosphatase 3 (MKP-3) is known to attenuate the ERK signaling pathway. It has been recently demonstrated that MKP-3 is also a player in promoting hepatic glucose output in obese state by interacting and activating FOXO1. Reduction of hepatic MKP-3 expression is sufficient to reduce blood glucose levels in both diet-induced and genetically obese mice. METHODOLOGY/PRINCIPAL FINDINGS: In current study, the mechanism of MKP-3/FOXO1 interaction and the effects on transcription of gluconeogenic gene and glucose output was investigated in Fao hepatoma cells by using mutated MKP-3 and FOXO1 adenoviral constructs. The results indicate that MKP-3 phosphatase activity is not required for MKP-3/FOXO1 interaction but is essential for FOXO1 nuclear translocation and MKP-3 promoted gluconeogenesis. Compared to GFP control (1+/-0.38), MKP-3 increased G6Pase gene expression by 242% (3.42+/-0.62) while inactive MKP-3 does not change G6Pase expression (0.98+/-0.17). The residues 200-260 of MKP-3 and the residues 360-456 of FOXO1 are essential for mediating MKP-3/FOXO1 interaction. Interestingly, ERK phosphorylation deficient but not Akt phosphorylation deficient FOXO1 mutant lost interaction with MKP-3. Furthermore, in vivo experiments showed that Akt phosphorylation resistant FOXO1 3A mutant is sufficient to rescue the hypoglycemia caused by MKP-3 knock down in the liver of lean mice (from 141+/-6.78 to 209+/-14.64 mg/dL). CONCLUSIONS/SIGNIFICANCE: 1) Critical residues mediating MKP-3/FOXO1 interaction have been identified; 2) ERK phosphorylation deficient FOXO1 mutant is as potent as Akt phosphorylation deficient FOXO1 mutant in activating transcription of gluconeogenic genes; 3) Constitutively active FOXO1 can rescue the hypoglycemic effect caused by reduced hepatic MKP-3 expression in vivo. |
