Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3{beta} Inactivation

doi:10.1126/science.1156037

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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

Abstract: Glycogen synthase kinase 3β (GSK3β) is involved inmetabolism, neurodegeneration, and cancer. Inhibition of GSK3βactivity is the primary mechanism that regulates this widelyexpressed active kinase. Although the protein kinase Akt inhibitsGSK3β by phosphorylation at the N terminus, preventingAkt-mediated phosphorylation does not affect the cell-survivalpathway activated through the GSK3β substrate β-catenin.Here, we show that p38 mitogen-activated protein kinase (MAPK)also inactivates GSK3β by direct phosphorylation at itsC terminus, and this inactivation can lead to an accumulationof β-catenin. p38 MAPK–mediated phosphorylation ofGSK3β occurs primarily in the brain and thymocytes. Activationof β-catenin–mediated signaling through GSK3βinhibition provides a potential mechanism for p38 MAPK–mediatedsurvival 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 Autónomade México, Cuernavaca, 62210, México.

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

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