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Science 320 (5876): 667-670

Copyright © 2008 by the American Association for the Advancement of Science

Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3β Inactivation

Tina M. Thornton,1 Gustavo Pedraza-Alva,1* Bin Deng,2,3 C. David Wood,1 Alexander Aronshtam,1 James L. Clements,4 Guadalupe Sabio,5 Roger J. Davis,5 Dwight E. Matthews,1,3 Bradley Doble,6 Mercedes Rincon1{dagger}

Abstract: Glycogen synthase kinase 3β (GSK3β) is involved in metabolism, neurodegeneration, and cancer. Inhibition of GSK3β activity is the primary mechanism that regulates this widely expressed active kinase. Although the protein kinase Akt inhibits GSK3β by phosphorylation at the N terminus, preventing Akt-mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3β substrate β-catenin. Here, we show that p38 mitogen-activated protein kinase (MAPK) also inactivates GSK3β by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of β-catenin. p38 MAPK–mediated phosphorylation of GSK3β occurs primarily in the brain and thymocytes. Activation of β-catenin–mediated signaling through GSK3β inhibition provides a potential mechanism for p38 MAPK–mediated survival in specific tissues.

1 Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405–0068, USA.
2 Department of Biology, University of Vermont, Burlington, VT 05405–0068, USA.
3 Department of Chemistry, University of Vermont, Burlington, VT 05405–0068, USA.
4 Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA.
5 Program in Molecular Medicine, University of Massachusetts, Worcester, MA 01605, USA.
6 McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario, L8N 3Z5, Canada.

* Present address: Departamento de Medicina Molecular y Bioprocesos, Instituto de Biotecnología, Universidad Nacional Autónoma de México, Cuernavaca, 62210, México.

{dagger} To whom correspondence should be addressed. E-mail: mrincon{at}uvm.edu

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