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J. Biol. Chem., Vol. 282, Issue 39, 28980-28990, September 28, 2007

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Mitogen-activated Protein Kinase p38 Regulates the Wnt/Cyclic GMP/Ca²⁺ Non-canonical Pathway^*

From the Departments of Physiology & Biophysics, Diabetes & Metabolic Diseases Research Center, School of Medicine, State University of New York/Stony Brook, Stony Brook, New York 11794-8661

The non-canonical Wnt/cyclic GMP/Ca²⁺/NF-AT pathway operates via Frizzled-2, a member of the superfamily of G protein-coupled receptors. In scanning for signaling events downstream of the Frizzled-2/Gt2/PDE6 triad activated in response to Wnt5a, we observed a strong activation of the mitogen-activated protein kinase p38 in mouse F9 teratocarcinoma embryonal cells. The activation of p38 is essential for NF-AT transcriptional activation mediated via Frizzled2. Wnt5a-stimulated p38 activation was rapid, sensitive to pertussis toxin, to siRNA against either Gt2 or p38, and to the p38 inhibitor SB203580. Real-time analysis of intracellular cyclic GMP using the Cygnet2 biosensor revealed p38 to act at the level of cyclic GMP, upstream of the mobilization of intracellular Ca²⁺. Fluorescence resonance energy transfer (FRET) imaging reveals the changes in cyclic GMP in response to Wnt5a predominate about the cell membrane, and likewise sensitive to either siRNA targeting p38 or to treatment with SB203580. Dishevelled is not required for Wnt5a activation of p38; siRNAs targeting Dishevelleds and expression of the Dishevelled antagonist Dapper-1 do not suppress the p38 response to Wnt5a stimulation. These novel results are the first to detail a Dishevelled-independent Wnt response, demonstrating a critical role of the mitogen-activated protein kinase p38 in regulating the Wnt non-canonical pathway.

Received for publication, April 3, 2007 , and in revised form, August 3, 2007.

^* This work was supported by Grant GM 069375 from the NIGMS, National Institutes of Health. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Dept. of Physiology & Biophysics, Diabetes & Metabolic Diseases Research Center, School of Medicine, SUNY/Stony Brook, Stony Brook, NY 11794-8661. Tel.: 631-444-3489; Fax: 631-444-3432; E-mail: wangh{at}pharm.stonybrook.edu.

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