Dataset Information

Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.

ABSTRACT: 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.

SUBMITTER: Thornton TM

PROVIDER: S-EPMC2597039 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

ACCESS DATA

Publications

Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.

Thornton Tina M TM 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

Science (New York, N.Y.) 20080501 5876

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) als ...[more]

PMID: 18451303

Similar Datasets

Project description:Initial Ca(2+)-dependent contraction of intestinal smooth muscle is inhibited upon IL-1beta treatment. The decrease in contraction reflects the upregulation of regulator of G protein signaling-4 (RGS4) via the canonical inhibitor of NF-kappaB kinase-2 (IKK2)/IkappaB-alpha/NF-kappaB pathway. Here, we show that the activation of various protein kinases, including ERK1/2, p38 MAPK, and phosphoinositide 3-kinase (PI3K), differentially modulates IL-1beta-induced upregulation of RGS4 in rabbit colonic muscle cells. IL-1beta treatment caused a transient phosphorylation of ERK1/2 and p38 MAPK. It also caused the phosphorylation of Akt and glycogen synthase kinase-3beta (GSK3beta), sequential downstream effectors of PI3K. Pretreatment with PD-98059 (an ERK inhibitor) and SB-203580 (a p38 MAPK inhibitor) significantly inhibited IL-1beta-induced RGS4 expression. In contrast, LY-294002 (a PI3K inhibitor) augmented, whereas GSK3beta inhibitors inhibited, IL-1beta-induced RGS4 expression. PD-98059 blocked IL-1beta-induced phosphorylation of IKK2, degradation of IkappaB-alpha, and phosphorylation and nuclear translocation of NF-kappaB subunit p65, whereas SB-203580 had a marginal effect, implying that the effect of ERK1/2 is exerted on the canonical IKK2/IkappaB-alpha/p65 pathway of NF-kappaB activation but that the effect of p38 MAPK may not predominantly involve NF-kappaB signaling. The increase in RGS4 expression enhanced by LY-294002 was accompanied by an increase in the phosphorylation of IKK2/IkappaB-alpha/p65 and blocked by pretreatment with inhibitors of IKK2 (IKK2-IV) and IkappaB-alpha (MG-132). Inhibition of GSK3beta abolished IL-1beta-induced phosphorylation of IKK2/p65. These findings suggest that ERK1/2 and p38 MAPK enhance IL-1beta-induced upregulation of RGS4; the effect of ERK1/2 reflects its ability to promote IKK2 phosphorylation and increase NF-kappaB activity. GSK3beta acts normally to augment the activation of the canonical NF-kappaB signaling. The PI3K/Akt/GSK3beta pathway attenuates IL-1beta-induced upregulation of RGS4 expression by inhibiting NF-kappaB activation.

Project description:BackgroundRenal interstitial fibrosis (RIF) is a common pathway to end-stage renal disease regardless of the initial etiology. Currently, the molecular mechanisms for RIF remains not fully elucidated. Nuclear receptor subfamily 4 group A member 1(Nr4a1), a member of the NR4A subfamily of nuclear receptors, is a ligand-activated transcription factor. The role of Nr4a1 in RIF remains largely unknown.MethodsIn this study, we determined the role and action mechanism of Nr4a1 in RIF. We used unilateral ureteral obstruction (UUO) mice and transforming growth factor (TGF)-β1-treated human renal proximal tubular epithelial cells (HK-2 cells) as in vivo and in vitro models of RIF. A specific Nr4a1 agonist Cytosporone B (Csn-B) was applied to activate Nr4a1 both in vivo and in vitro, and Nr4a1 small interfering RNA was applied in vitro. Renal pathological changes were evaluated by hematoxylin and eosin and Masson staining, and the expression of fibrotic proteins including fibronectin (Fn) and collagen-I (Col-I), and phosphorylated p38 MAPK was measure by immunohistochemical staining and western blot analysis.ResultsThe results showed that Nr4a1 was upregulated in UUO mouse kidneys, and was positively correlated with the degree of interstitial kidney injury and the levels of fibrotic proteins. Csn-B treatment aggravated UUO-induced renal interstitial fibrosis, and induced p38 MAPK phosphorylation. In vitro, TGF-β induced Nr4a1 expression, and Nr4a1 downregulation prevented TGF-β1-induced expression of Fn and Col-I and the activation of p38 MAPK. Csn-B induced fibrotic proteins expression and p38 MAPK phosphorylation, and moreover Csn-B induced fibrotic proteins expression was abrogated by treatment with p38 MAPK inhibitor SB203580. We provided further evidence that Csn-B treatment promoted cytoplasmic accumulation of Nr4a1.ConclusionThe findings in the present study indicate that Nr4a1 promotes renal fibrosis potentially through activating p38 MAPK kinase.

Dataset Information

Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.

Publications

Phosphorylation by p38 MAPK as an alternative pathway for GSK3beta inactivation.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets