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Treatment of cells with the angiogenic inhibitor fumagillin results in increased stability of eukaryotic initiation factor 2-associated glycoprotein, p67, and reduced phosphorylation of extracellular signal-regulated kinases.

Biochemistry | Nov 23, 2004

http://www.ncbi.nlm.nih.gov/pubmed/15544353

Fumagillin, an angiogenic inhibitor, binds to methionine aminopeptidase 2, which is the same as eukaryotic initiation factor 2-associated glycoprotein, p67. p67 protects eIF2alpha from phosphorylation by its kinases. To understand the importance of fumagillin binding to p67, we measured the level of p67 in mouse C2C12 myoblasts treated with fumagillin. We show that fumagillin increases the stability of p67 by decreasing its turnover rate. The increased levels of p67 result in inhibition of phosphorylation of extracellular signal-regulated kinases 1 and 2 (ERKs 1 and 2). p67 binds to these ERKs, and the 108-480 amino acid segment is sufficient for this binding. p67's affinity to ERKs 1 and 2 also increases in fumagillin-treated myoblasts while its affinity for eIF2alpha remains unchanged. A mutant at the conserved amino acid residue D251A increases the phosphorylation of ERKs 1 and 2 without affecting the binding to p67, thus indicating the importance of this residue in the regulation of the phosphorylation of these ERKs. These results suggest that fumagillin increases the stability of p67 and its affinity to ERKs 1 and 2 and causes the inhibition of the phosphorylation of ERKs 1 and 2.

Pubmed ID: 15544353 RIS Download

Mesh terms: Alanine | Amino Acid Substitution | Aminopeptidases | Angiogenesis Inhibitors | Animals | Aspartic Acid | Cell Line | Cyclohexanes | Enzyme Inhibitors | Enzyme Stability | Eukaryotic Initiation Factor-2 | Fatty Acids, Unsaturated | Female | Glycoproteins | Inhibitory Concentration 50 | Mice | Mice, Inbred BALB C | Mitogen-Activated Protein Kinase 1 | Mitogen-Activated Protein Kinase 3 | Myoblasts, Skeletal | Peptide Fragments | Phosphorylation | Protein Binding | Sesquiterpenes | Transfection

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Associated grants

  • Agency: NIGMS NIH HHS, Id: GM59190

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