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GSK3beta is involved in JNK2-mediated beta-catenin inhibition.

Hu D, Bi X, Fang W, Han A, Yang W - PLoS ONE (2009)

Bottom Line: Additionally, physical interaction and co-localization among JNK2, beta-catenin and GSK3beta were observed by immunoprecipitation, mammalian two-hybridization assay and confocal microscopy, respectively.In general, our data suggested that JNK2, like JNK1, interacts with and suppresses beta-catenin signaling in vitro and in vivo, in which GSK3beta plays a key role, although previous studies have shown distinct functions of JNK1 and JNK2.Our study also provides a novel insight into the crosstalk between Wnt/beta-catenin and MAPK JNKs signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.

ABSTRACT

Background: We have recently reported that mitogen-activated protein kinase (MAPK) JNK1 downregulates beta-catenin signaling and plays a critical role in regulating intestinal homeostasis and in suppressing tumor formation. This study was designed to determine whether JNK2, another MAPK, has similar and/or different functions in the regulation of beta-catenin signaling.

Methodology and principal findings: We used an in vitro system with manipulation of JNK2 and beta-catenin expression and found that activated JNK2 increased GSK3beta activity and inhibited beta-catenin expression and transcriptional activity. However, JNK2-mediated downregulation of beta-catenin was blocked by the proteasome inhibitor MG132 and GSK3beta inhibitor lithium chloride. Moreover, targeted mutations at GSK3beta phosphorylation sites (Ser33 and Ser37) of beta-catenin abrogated JNK2-mediated suppression of beta-catenin. In vivo studies further revealed that JNK2 deficiency led to upregulation of beta-catenin and increase of GSK3-beta phosphorylation in JNK2-/- mouse intestinal epithelial cells. Additionally, physical interaction and co-localization among JNK2, beta-catenin and GSK3beta were observed by immunoprecipitation, mammalian two-hybridization assay and confocal microscopy, respectively.

Conclusion and significance: In general, our data suggested that JNK2, like JNK1, interacts with and suppresses beta-catenin signaling in vitro and in vivo, in which GSK3beta plays a key role, although previous studies have shown distinct functions of JNK1 and JNK2. Our study also provides a novel insight into the crosstalk between Wnt/beta-catenin and MAPK JNKs signaling.

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Related in: MedlinePlus

JNK2 deficiency caused upregulation of β-catenin and its downstream target CDK4, as well as upregulation of GSK3β phosphorylation in JNK2-/- mouse intestinal epithelial cells, compared to those in JNK2+/+ mice.Each lane represents one mouse. β-actin served as loading control.
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pone-0006640-g004: JNK2 deficiency caused upregulation of β-catenin and its downstream target CDK4, as well as upregulation of GSK3β phosphorylation in JNK2-/- mouse intestinal epithelial cells, compared to those in JNK2+/+ mice.Each lane represents one mouse. β-actin served as loading control.

Mentions: To validate the regulation β-catenin by JNK2 in vivo, JNK2-/- and +/+ mice were dissected. As shown in figure 4, β-catenin and its downstream target CDK4 were upregulated in intestinal epithelial cells from JNK2-/- mice, compared to the JNK2+/+ mice. Consistently, phosphorylated GSK3β was upregulated although total GSK3β was not changed. The in vivo data provided additional evidence that GSK3β is involved in JNK2-mediated β-catenin regulation.


GSK3beta is involved in JNK2-mediated beta-catenin inhibition.

Hu D, Bi X, Fang W, Han A, Yang W - PLoS ONE (2009)

JNK2 deficiency caused upregulation of β-catenin and its downstream target CDK4, as well as upregulation of GSK3β phosphorylation in JNK2-/- mouse intestinal epithelial cells, compared to those in JNK2+/+ mice.Each lane represents one mouse. β-actin served as loading control.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2721980&req=5

pone-0006640-g004: JNK2 deficiency caused upregulation of β-catenin and its downstream target CDK4, as well as upregulation of GSK3β phosphorylation in JNK2-/- mouse intestinal epithelial cells, compared to those in JNK2+/+ mice.Each lane represents one mouse. β-actin served as loading control.
Mentions: To validate the regulation β-catenin by JNK2 in vivo, JNK2-/- and +/+ mice were dissected. As shown in figure 4, β-catenin and its downstream target CDK4 were upregulated in intestinal epithelial cells from JNK2-/- mice, compared to the JNK2+/+ mice. Consistently, phosphorylated GSK3β was upregulated although total GSK3β was not changed. The in vivo data provided additional evidence that GSK3β is involved in JNK2-mediated β-catenin regulation.

Bottom Line: Additionally, physical interaction and co-localization among JNK2, beta-catenin and GSK3beta were observed by immunoprecipitation, mammalian two-hybridization assay and confocal microscopy, respectively.In general, our data suggested that JNK2, like JNK1, interacts with and suppresses beta-catenin signaling in vitro and in vivo, in which GSK3beta plays a key role, although previous studies have shown distinct functions of JNK1 and JNK2.Our study also provides a novel insight into the crosstalk between Wnt/beta-catenin and MAPK JNKs signaling.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.

ABSTRACT

Background: We have recently reported that mitogen-activated protein kinase (MAPK) JNK1 downregulates beta-catenin signaling and plays a critical role in regulating intestinal homeostasis and in suppressing tumor formation. This study was designed to determine whether JNK2, another MAPK, has similar and/or different functions in the regulation of beta-catenin signaling.

Methodology and principal findings: We used an in vitro system with manipulation of JNK2 and beta-catenin expression and found that activated JNK2 increased GSK3beta activity and inhibited beta-catenin expression and transcriptional activity. However, JNK2-mediated downregulation of beta-catenin was blocked by the proteasome inhibitor MG132 and GSK3beta inhibitor lithium chloride. Moreover, targeted mutations at GSK3beta phosphorylation sites (Ser33 and Ser37) of beta-catenin abrogated JNK2-mediated suppression of beta-catenin. In vivo studies further revealed that JNK2 deficiency led to upregulation of beta-catenin and increase of GSK3-beta phosphorylation in JNK2-/- mouse intestinal epithelial cells. Additionally, physical interaction and co-localization among JNK2, beta-catenin and GSK3beta were observed by immunoprecipitation, mammalian two-hybridization assay and confocal microscopy, respectively.

Conclusion and significance: In general, our data suggested that JNK2, like JNK1, interacts with and suppresses beta-catenin signaling in vitro and in vivo, in which GSK3beta plays a key role, although previous studies have shown distinct functions of JNK1 and JNK2. Our study also provides a novel insight into the crosstalk between Wnt/beta-catenin and MAPK JNKs signaling.

Show MeSH
Related in: MedlinePlus