Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3β Inactivation

American Association for the Advancement of Science (AAAS) - Tập 320 Số 5876 - Trang 667-670 - 2008
Tina M. Thornton1,2,3,4,5, Gustavo Pedraza‐Alva1,2,3,4,5, Bin Deng1,2,3,4,5, C. David Wood1,2,3,4,5, Alexander Aronshtam1,2,3,4,5, James L. Clements1,2,3,4,5, Guadalupe Sabio1,2,3,4,5, Roger J. Davis1,2,3,4,5, Dwight E. Matthews1,2,3,4,5, Bradley W. Doble1,2,3,6,5, Mercedes Rincón1,2,3,4,5
1Department of Biology, University of Vermont, Burlington, VT 05405–0068, USA.
2Department of Chemistry, University of Vermont, Burlington, VT 05405–0068, USA.
3Department of Immunology, Roswell Park Cancer Institute, Buffalo, NY 14263, USA
4Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405–0068, USA.
5Program in Molecular Medicine, University of Massachusetts, Worcester, MA 01605, USA.
6McMaster Stem Cell and Cancer Research Institute, McMaster University, Hamilton, Ontario L8N 3Z5, Canada

Tóm tắt

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.

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Tài liệu tham khảo

10.1038/sj.cr.7290257

10.4161/cc.4.1.1357

10.1074/jbc.M001020200

10.1007/s10495-005-3372-z

10.1016/j.ccr.2006.11.024

10.1073/pnas.231623498

10.1084/jem.191.2.321

10.1038/sj.emboj.7600972

10.1038/90623

10.1038/ni0901-863

10.1038/sj.onc.1205400

Materials and methods are available as supporting material on Science Online.

10.1126/science.281.5382.1509

10.1074/jbc.M107977200

10.1016/S0092-8674(02)00685-2

10.1136/jcp.2003.009506

10.1038/378785a0

10.1016/j.devcel.2007.04.001

10.1242/jcs.00384

10.1016/j.molcel.2005.06.009

10.1016/S0092-8674(01)00374-9

10.1042/bj3590001

10.1101/gad.1107303

10.1038/sj.emboj.7600633

We thank C. Charland for flow cytometry analysis and cell sorting T. Hunter and the DNA Sequencing Facility for sequencing and the Univ. of Vermont Protein Core Facility for peptide synthesis. This work was supported by NIH grants R01 AI051454 and National Center for Research Resources (NCRR) grant P20 RR15557 (M.R.) NCRR grants P20 RR021905 and P20 RR16462 (D.E.M.) and Canada Research Chairs and Canadian Institutes of Health Research grant MOP-85057 (B.D.).

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American Association for the Advancement of Science (AAAS)

Tập 320 Số 5876

667-670

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