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PLoS One. 2009 Aug 13;4(8):e6640. doi: 10.1371/journal.pone.0006640.

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

Author information

1
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.

PMID:
19675674
PMCID:
PMC2721980
DOI:
10.1371/journal.pone.0006640
[Indexed for MEDLINE]
Free PMC Article

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