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


RESULTS
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.


CONCLUSIONS
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.
Hu
Dong
D
Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.
Bi
Xiuli
X
Fang
Wenfeng
W
Han
Anjia
A
Yang
Wancai
W
D000818:Animals; D015153:Blotting, Western; D002460:Cell Line; D051358:Cyclin-Dependent Kinase 4 / Q000378:metabolism; D015536:Down-Regulation; D004791:Enzyme Inhibitors / Q000494:pharmacology; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D047468:Immunoprecipitation; D007976:Leupeptins / Q000494:pharmacology; D051379:Mice; D018345:Mice, Knockout; D048056:Mitogen-Activated Protein Kinase 9 / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation; D014158:Transcription, Genetic; D015854:Up-Regulation; D051176:beta Catenin / Q000037:antagonists & inhibitors*
D004791:Enzyme Inhibitors; D007976:Leupeptins; D051176:beta Catenin; D048056:Mitogen-Activated Protein Kinase 9; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605507:Gsk3b protein, mouse; D051358:Cyclin-Dependent Kinase 4; D038362:Glycogen Synthase Kinase 3; C072553:benzyloxycarbonylleucyl-leucyl-leucine aldehyde
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