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Enhanced phosphorylation of FOXO and GSK‐3 by organo‐vanadium complexes: potential role in insulino‐mimesis
Author(s) -
Vardatsikos George,
Mehdi Mohamad Z,
Srivastava Ashok K
Publication year - 2008
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.22.1_supplement.614.10
Subject(s) - phosphoenolpyruvate carboxykinase , gsk 3 , phosphorylation , foxo1 , chemistry , wortmannin , glycogen synthase , chinese hamster ovary cell , kinase , microbiology and biotechnology , insulin receptor , gsk3b , protein kinase b , pi3k/akt/mtor pathway , signal transduction , insulin , biochemistry , medicine , enzyme , endocrinology , biology , receptor , insulin resistance
Several organo‐vanadium complexes (OVCs) have been shown to exert multiple insulino‐mimetic effects in rodent models of diabetes. We have shown that Bis(maltolato) OxoVanadium(IV) (BMOV) activates several components of the insulin signaling pathway such as phosphatidyl inositol‐3 kinase (PI3‐K) and protein kinase B (PKB). Forkhead Box Proteins (FOXO) and Glycogen Synthase Kinase‐3 (GSK‐3), downstream substrates of PKB, are thought to contribute to insulin‐induced gene expression of key gluconeogenic enzymes such as phosphoenolpyruvate carboxykinase (PEPCK) and glucose‐6‐phosphatase (G6Pase). OVCs are known to modulate the expression of PEPCK and G6Pase, hence in the present studies we investigated BMOV‐induced FOXO and GSK‐3 regulation. Treatment of Chinese hamster ovary cells overexpressing human insulin receptor (CHO‐HIR) enhanced FOXO and GSK‐3 phosphorylation. Wortmannin, a PI3‐K inhibitor, decreased FOXO and GSK‐3 phosphorylation induced by both insulin and OVCs, as did AG1024, an inhibitor of IR/IGF‐1R‐PTK activity. In summary, these data demonstrate that OVCs potently enhance the phosphorylation of FOXO and GSK‐3 via IGF‐1R‐PTK/PI3K‐dependent pathways, suggesting that OVCs may contribute towards the insulino‐mimetic effects of BMOV by transcription regulation of gluconeogenic enzymes. (Supported by grants from Canadian Institutes of Health Research).