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Phosphorylation and inactivation of glycogen synthase kinase 3 by protein kinase A.

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.

Pubmed ID: 11035810


  • Fang X
  • Yu SX
  • Lu Y
  • Bast RC
  • Woodgett JR
  • Mills GB


Proceedings of the National Academy of Sciences of the United States of America

Publication Data

October 24, 2000

Associated Grants

  • Agency: NCI NIH HHS, Id: CA64602
  • Agency: NCI NIH HHS, Id: CA82716

Mesh Terms

  • Animals
  • Calcium-Calmodulin-Dependent Protein Kinases
  • Cell Line
  • Cyclic AMP
  • Cyclic AMP-Dependent Protein Kinases
  • Enzyme Activation
  • Glycogen Synthase Kinase 3
  • Glycogen Synthase Kinases
  • Humans
  • Phosphatidylinositol 3-Kinases
  • Phosphorylation
  • Protein Binding
  • Protein-Serine-Threonine Kinases
  • Proto-Oncogene Proteins
  • Proto-Oncogene Proteins c-akt