Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.
Glycogen synthase kinase 3beta (GSK3beta) is involved in metabolism, neurodegeneration, and cancer. Inhibition of GSK3beta activity is the primary mechanism that regulates this widely expressed active kinase. Although the protein kinase Akt inhibits GSK3beta by phosphorylation at the N terminus, preventing Akt-mediated phosphorylation does not affect the cell-survival pathway activated through the GSK3beta substrate beta-catenin. Here, we show that p38 mitogen-activated protein kinase (MAPK) also inactivates GSK3beta by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of beta-catenin. p38 MAPK-mediated phosphorylation of GSK3beta occurs primarily in the brain and thymocytes. Activation of beta-catenin-mediated signaling through GSK3beta inhibition provides a potential mechanism for p38 MAPK-mediated survival in specific tissues.
Thornton
Tina M
TM
Department of Medicine/Immunobiology Program, University of Vermont, Burlington, VT 05405-0068, USA.
Pedraza-Alva
Gustavo
G
Deng
Bin
B
Wood
C David
CD
Aronshtam
Alexander
A
Clements
James L
JL
Sabio
Guadalupe
G
Davis
Roger J
RJ
Matthews
Dwight E
DE
Doble
Bradley
B
Rincon
Mercedes
M
D000818:Animals; D001921:Brain / Q000201:enzymology; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000276:immunology / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D051379:Mice; D010766:Phosphorylation; D047428:Protein Kinase Inhibitors / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D012694:Serine / Q000378:metabolism; D013950:Thymus Gland / Q000166:cytology / Q000201:enzymology; D051176:beta Catenin / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D051176:beta Catenin; D012694:Serine; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051057:Proto-Oncogene Proteins c-akt; D048051:p38 Mitogen-Activated Protein Kinases; D038362:Glycogen Synthase Kinase 3