Phosphorylation by p38 MAPK as an Alternative Pathway for GSK3β Inactivation

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.The p38 mitogen-activated protein kinase (MAPK) is activated through phosphorylation primarily by MAPK kinase 3 (MKK3) and MKK6 in response to cellular stress and cytokines. The p38 MAPK pathway functions in the control of differentiation, the blockade of proliferation, and in the induction of apoptosis (1). It is also activated in response to DNA double-stranded breaks (DSBs) induced by ionizing irradiation or chemotherapeutic drugs, and it participates in the induction of a G 2 /M cell-cycle checkpoint (2,3). p38 MAPK can also promote survival (4-6) by unknown mechanisms. During T cell receptor β (TCRβ) rearrangement, V(D)J recombination-mediated DSBs also activate p38 MAPK in immature thymocytes at the double negative 3 (DN3) stage of development (7,8). The expression of a constitutively active mutant of MKK6 [MKK6(Glu)] in thymocytes of transgenic mice (MKK6 transgenic mice) activates a p53-mediated G 2 /M phase cell-cycle checkpoint (8). Like recombination-activating gene (Rag) deficiency, persistent activation of p38 MAPK interferes with the differentiation of thymocytes beyond the DN3 stage. However, MKK6 transgenic thymocytes (but not Rag -/-thymocytes) survive and accumulate in vivo (8), suggesting that

Mechanisms of RON-mediated epithelial-mesenchymal transition in MDCK cells through the MAPK pathway

“…MSP further regulated RON phosphorylation, leading to the activation of downstream signaling proteins such as Erk1/2 and GSK-3β (Figure 4). The results indicated that the activation of Erk1/2 stimulated with RON can lead to the increased expression of p-GSK-3β, in agreement with previous results (20,21). It has been reported that MAPK can inactivate GSK-3β by direct phosphorylation at its C terminus (21).…”

Increased numbers of thymic and peripheral CD4+ CD25+Foxp3+ cells in the absence of CD5 signaling

“…Recently, it has been described that P38 may have a role in thymocyte survival by promoting the inactivation of GSK3b through an Akt-independent mechanism [70]. In this context, recent data from our group (Nava et al unpublished results) indicate that thymus-derived antigen-specific Treg show increased phosphorylation of P38 in response to CD3 crosslinking, compared with naïve antigen-specific T cells.…”

Adiponectin as a tissue regenerating hormone: more than a metabolic function

“…In turn, p38 MAPK leads to the inhibitory phosphorylation on Ser-389 of glycogen synthase kinase 3β. The final effect is the nuclear accumulation of β catenin, a well-reported glycogen synthase kinase 3β substrate [75,76]. Fig.…”

“…In skeletal muscle, gAd promotes the differentiation of myoblasts into myotubes [40]. In the kidney, fAd acts by inhibiting apoptosis in podocytes and by supporting renal recovery [76]. Depletion of fAd in murine liver leads to a decrease in mass growth and hepatocyte proliferation [74] and an increase in lipid accumulation [75].…”