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GSK3beta is involved in JNK2-mediated beta-catenin inhibition

Dong Hu1, Xiuli Bi, Wenfeng Fang

  • 1Department of Pathology, University of Illinois at Chicago, Chicago, Illinois, United States of America.

Plos One
|August 14, 2009
PubMed
Abstract

Insights

Mitogen-activated protein kinase (MAPK) JNK2 suppresses beta-catenin signaling, similar to JNK1. This interaction, crucial for intestinal homeostasis and tumor suppression, involves glycogen synthase kinase 3 beta (GSK3beta).

Area of Science:

  • Cellular Biology
  • Molecular Biology
  • Oncology

Background:

  • Mitogen-activated protein kinase (MAPK) JNK1 was previously shown to downregulate beta-catenin signaling.
  • JNK1 plays a critical role in intestinal homeostasis and tumor suppression.
  • The function of the related MAPK, JNK2, in beta-catenin signaling regulation was investigated.

Purpose of the Study:

  • To determine if JNK2 has similar or different functions compared to JNK1 in regulating beta-catenin signaling.
  • To elucidate the molecular mechanisms underlying JNK2's regulation of beta-catenin.

Main Methods:

  • In vitro studies involving manipulation of JNK2 and beta-catenin expression.
  • Use of proteasome and GSK3beta inhibitors (MG132, lithium chloride).
  • In vivo studies using JNK2 knockout mice and various biochemical assays (immunoprecipitation, mammalian two-hybridization, confocal microscopy).

Main Results:

  • Activated JNK2 increased GSK3beta activity, inhibiting beta-catenin expression and transcriptional activity.
  • JNK2-mediated beta-catenin downregulation was dependent on proteasome activity and GSK3beta.
  • JNK2 deficiency in mice led to beta-catenin upregulation and increased GSK3beta phosphorylation in intestinal cells.
  • Physical interaction and co-localization of JNK2, beta-catenin, and GSK3beta were confirmed.

Conclusions:

  • JNK2, like JNK1, interacts with and suppresses beta-catenin signaling both in vitro and in vivo.
  • Glycogen synthase kinase 3 beta (GSK3beta) plays a key role in JNK2-mediated beta-catenin suppression.
  • The findings reveal a novel crosstalk between Wnt/beta-catenin and MAPK JNK signaling pathways.

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