title: Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A.
abstract: Glycogen synthase kinase 3 (GSK-3) is implicated in multiple biological processes including metabolism, gene expression, cell fate determination, proliferation, and survival. GSK-3 activity is inhibited through phosphorylation of serine 21 in GSK-3 alpha and serine 9 in GSK-3 beta. These serine residues of GSK-3 have been previously identified as targets of protein kinase B (PKB/Akt), a serine/threonine kinase located downstream of phosphatidylinositol 3-kinase. Here, we show that serine 21 in GSK-3 alpha and serine 9 in GSK-3 beta are also physiological substrates of cAMP-dependent protein kinase A. Protein kinase A physically associates with, phosphorylates, and inactivates both isoforms of GSK-3. The results indicate that depending on the stimulatory context, the activity of GSK-3 can be modulated either by growth factors that work through the phosphatidylinositol 3-kinase-protein kinase B cascade or by hormonal stimulation of G protein-coupled receptors that link to changes in intracellular cAMP levels.
authors.affiliation: Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
authors.forename: X
authors.initials: X
authors.lastname: Fang
authors.forename: S X
authors.initials: SX
authors.lastname: Yu
authors.forename: Y
authors.initials: Y
authors.lastname: Lu
authors.forename: R C
authors.initials: RC
authors.lastname: Bast
authors.forename: J R
authors.initials: JR
authors.lastname: Woodgett
authors.forename: G B
authors.initials: GB
authors.lastname: Mills
mesh_terms: D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D002460:Cell Line; D000242:Cyclic AMP / Q000378:metabolism; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism*; D004789:Enzyme Activation; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D006801:Humans; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt
chemical_list: D017871:Calcium-Calmodulin-Dependent Protein Kinases; D000242:Cyclic AMP; D017868:Cyclic AMP-Dependent Protein Kinases; D038362:Glycogen Synthase Kinase 3; D038341:Glycogen Synthase Kinases; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; C494918:AKT1 protein, human