Phosphorylation by p38 MAPK as an alternative pathway for GSK3β inactivation

Glycogen synthase kinase 3 beta (GSK3 beta) is involved in metabolism, neurodegeneration, and cancer. Inhibition of GSK3 beta activity is the primary mechanism that regulates this widely expressed active kinase. Although the protein kinase Akt inhibits GSK3 beta by phosphorylation at the N terminus, preventing Akt- mediated phosphorylation does not affect the cell- survival pathway activated through the GSK3 beta substrate beta- catenin. Here, we show that p38 mitogen- activated protein kinase ( MAPK) also inactivates GSK3 beta by direct phosphorylation at its C terminus, and this inactivation can lead to an accumulation of beta- catenin. p38 MAPK- mediated phosphorylation of GSK3 beta occurs primarily in the brain and thymocytes. Activation of beta- catenin- mediated signaling through GSK3 beta inhibition provides a potential mechanism for p38 MAPK- mediated survival in specific tissues.