spacer gif spacer gif spacer gif spacer gif spacer gif
QUICK SEARCH:   [advanced]


spacer gif
     Home     Help     Feedback     Subscriptions     Archive     Search     Table of Contents    

First published online October 22, 2008
doi: 10.1242/10.1242/jcs.032854

Journal of Cell Science 121, 3598-3607 (2008)
Published by The Company of Biologists 2008
This Article
Right arrow Figures Only
Right arrow Full Text
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow reprints & permissions
Google Scholar
Right arrow Articles by Bikkavilli, R. K.
Right arrow Articles by Malbon, C. C.
PubMed
Right arrow PubMed Citation
Right arrow Articles by Bikkavilli, R. K.
Right arrow Articles by Malbon, C. C.

Research Article

p38 mitogen-activated protein kinase regulates canonical Wnt–β-catenin signaling by inactivation of GSK3β

Rama Kamesh Bikkavilli*, Michael E. Feigin and Craig C. Malbon

Department of Pharmacology, Health Sciences Center, State University of New York at Stony Brook, Stony Brook, NY 11794-8651, USA

* Author for correspondence (e-mail: kamesh{at}pharm.stonybrook.edu)

Accepted 5 August 2008

The Wnt–β-catenin canonical signaling pathway is crucial for normal embryonic development, and aberrant expression of components of this pathway results in oncogenesis. Upon scanning for the mitogen-activated protein kinase (MAPK) pathways that might intersect with the canonical Wnt–β-catenin signaling pathway in response to Wnt3a, we observed a strong activation of p38 MAPK in mouse F9 teratocarcinoma cells. Wnt3a-induced p38 MAPK activation was sensitive to siRNAs against G{alpha}q or G{alpha}s, but not against either G{alpha}o or G{alpha}11. Activation of p38 MAPK is critical for canonical Wnt–β-catenin signaling. Chemical inhibitors of p38 MAPK (SB203580 or SB239063) and expression of a dominant negative-version of p38 MAPK attenuate Wnt3a-induced accumulation of β-catenin, Lef/Tcf-sensitive gene activation, and primitive endoderm formation. Furthermore, epistasis experiments pinpoint p38 MAPK as operating downstream of Dishevelleds. We also demonstrate that chemical inhibition of p38 MAPK restores Wnt3a-attenuated GSK3β kinase activity. We demonstrate the involvement of G-proteins and Dishevelleds in Wnt3a-induced p38 MAPK activation, highlighting a critical role for p38 MAPK in canonical Wnt–β-catenin signaling.

Key words: Wnt, β-catenin, p38 MAPK, Frizzled, Dishevelled, Canonical pathway, Lef/Tcf, Primitive endoderm, G-protein






© The Company of Biologists Ltd 2008