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

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

^*Department of Molecular Therapeutics, University of Texas M. D. Anderson Cancer Center, Houston, TX 77030; and ^†Department of Molecular and Medical Genetics, Ontario Cancer Institute and University of Toronto, Toronto, ON, Canada, M5G 2M9

Communicated by Louis Siminovitch, Mount Sinai Hospital, Toronto, Canada (received for review May 8, 2000)

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-3α and serine 9 in GSK-3β. 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-3α and serine 9 in GSK-3β 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.

Footnotes

↵ ‡ To whom reprint requests should be addressed. E-mail: gmills{at}notes.mdacc.tmc.edu.
Article published online before print: Proc. Natl. Acad. Sci. USA, 10.1073/pnas.220413597.
Article and publication date are at www.pnas.org/cgi/doi/10.1073/pnas.220413597
Abbreviations:

GSK-3,

glycogen synthase kinase 3;

PKA,

protein kinase A;

PKB,

protein kinase B;

PI3K,

phosphatidylinositol 3-kinase;

8-Br-cAMP,

8-bromo-cAMP;

8-Br-cGMP,

8-bromo-cGMP;

IGF-1,

insulin-like growth factor 1.