title: Molecular pathways leading to oxidative stress-induced phosphorylation of Akt.
abstract: Oxidative stress can activate a variety of intracellular signaling pathways. The authors previously reported the CaM-K inhibitor KN-93 inhibited hydrogen peroxide-induced phosphorylation of Akt on threonine 308 (T308). In this report they demonstrate that phosphorylation of T308 in response to hydrogen peroxide treatment is not inhibited by LY294002, suggesting that phosphorylation of this residue in response to oxidative stress is largely PI3K independent. In contrast, hydrogen peroxide-induced phosphorylation of Akt on serine 473 (S473) was downregulated by both PI3K and CaM-K inhibition, indicating that hydrogen peroxideinduced phosphorylation of Akt on S473 was largely dependent on both PI3K and a CaM-K activity. Further, it is reported that p56(Lck) had a substantial role in hydrogen peroxide-induced phosphorylation of S473, but only a minimal role in hydrogen peroxide-induced phosphorylation of T308. These data suggest that in response to hydrogen peroxide, two pathways are activated in Jurkat T lymphocytes that converge to result in the phosphorylation of Akt on S473 and T308. One pathway involves the CaM-Ks that may directly phosphorylate Akt on T308. In this pathway, neither the Src kinases nor PI3K are required. The other pathway mediated by hydrogen peroxide results in the phosphorylation of Akt on S473 and requires CaM-K, PI3K, and Src activity.
authors.affiliation: Department of Microbiology and Immunology, Brody School of Medicine at East Carolina University, Greenville, North Carolina 27834, USA.
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Lahair
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Howe
authors.forename: Oswaldo
authors.initials: O
authors.lastname: Rodriguez-Mora
authors.forename: James A
authors.initials: JA
authors.lastname: McCubrey
authors.forename: Richard A
authors.initials: RA
authors.lastname: Franklin
mesh_terms: D001596:Benzylamines / Q000494:pharmacology; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D002227:Carbazoles / Q000494:pharmacology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors; D005419:Flavonoids / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D006861:Hydrogen Peroxide / Q000494:pharmacology; D026121:Indole Alkaloids; D019169:Jurkat Cells; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck) / Q000172:deficiency / Q000378:metabolism; D008954:Models, Biological; D009025:Morpholines / Q000494:pharmacology; D018384:Oxidative Stress / Q000502:physiology*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology*; D013449:Sulfonamides / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000378:metabolism; D000096926:Benzenesulfonamides
chemical_list: D001596:Benzylamines; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D002227:Carbazoles; D002867:Chromones; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D005419:Flavonoids; D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D006861:Hydrogen Peroxide; D026121:Indole Alkaloids; D019860:Lymphocyte Specific Protein Tyrosine Kinase p56(lck); D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D047428:Protein Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D013449:Sulfonamides; C072105:KN 93; D000096926:Benzenesulfonamides; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C049985:staurosporine aglycone; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one