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J. Biol. Chem., Vol. 282, Issue 36, 26490-26502, September 7, 2007

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Inositol Pentakisphosphate Mediates Wnt/-Catenin Signaling^*

From the Department of Physiology and Biophysics, Diabetes and Metabolic Disease Research Center, School of Medicine, Health Sciences Center, State University of New York, Stony Brook, New York 11794-8661

Wnt3a stimulates lymphoid enhancer factor/T-cell factor protein-sensitive transcription, i.e. the canonical pathway, in mouse F9 embryonal tetratocarcinoma cells expressing rat Frizzled-1. We explored the potential roles for inositol polyphosphates as mediators of Wnt signaling in the canonical path-way. Wnt3a triggers G-protein-linked phosphatidylinositol signaling, transiently generating inositol polyphosphates, especially inositol pentakisphosphate (IP₅) accumulation. Knock-down of G_q abolishes, whereas expression of the Q209L constitutively active mutant of G_q mimics, the effects of Wnt3a on IP₅ generation and downstream signaling. Phospholipase C-1 and C-3 mediate the G protein signal to the level of phosphatidylinositol signaling. Knock-down and inhibitor studies of the enzymes responsible for generating IP₅ reveal inositol 1,4,5-trisphosphate 3-kinase and inositol polyphosphate multikinase as key mediators in the production of IP₅. Wnt3a stimulation of the canonical pathway requires accumulation of IP₅, which acts to inhibit the activity of glycogen synthase kinase-3, whereas stimulating casein kinase 2. Blockade of Wnt3a stimulation of IP₅ generation blocks -catenin accumulation, activation of lymphoid enhancer factor/T-cell factor protein-sensitive transcription, and promotion of primitive endoderm formation in response to Wnt3a. Phosphatidylinositol signaling mediates Wnt3a action in the canonical pathway, acting to generate inositol pentakisphosphate, a key second messenger of Wnt3a.

Received for publication, March 12, 2007 , and in revised form, June 26, 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.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. S1-S4.

¹ To whom correspondence should be addressed. Tel.: 631-444-3489; Fax: 631-444-3432; E-mail: wangh{at}pharm.stonybrook.edu.

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