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J. Biol. Chem., Vol. 280, Issue 3, 1911-1920, January 21, 2005

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The Pathway for the Production of Inositol Hexakisphosphate in Human Cells^*

John W. Verbsky, Shao-Chun Chang, Monita P. Wilson, Yasuhiro Mochizuki¶, and Philip W. Majerus||

From the Department of Internal Medicine, Division of Hematology, Washington University School of Medicine, St. Louis, Missouri 63110 and the ^¶Laboratory of Molecular Cell Biology, School of Life Science, Tokyo University of Pharmacy and Life Science, 1432-1 Horinouchi, Hachioji, Tokyo 192-0392, Japan

The yeast and Drosophila pathways leading to the production of inositol hexakisphosphate (InsP₆) have been elucidated recently. The in vivo pathway in humans has been assumed to be similar. Here we show that overexpression of Ins(1,3,4)P₃ 5/6-kinase in human cell lines results in an increase of inositol tetrakisphosphate (InsP₄) isomers, inositol pentakisphosphate (InsP₅) and InsP₆, whereas its depletion by RNA interference decreases the amounts of these inositol phosphates. Expression of Ins(1,3,4,6)P₄ 5-kinase does not increase the amount of InsP₅ and InsP₆, although its depletion does block InsP₅ and InsP₆ production, showing that it is necessary for production of InsP₅ and InsP₆. Expression of Ins(1,3,4,5,6)P₅ 2-kinase increases the amount of InsP₆ by depleting the InsP₅ in the cell, and depletion of 2-kinase decreases the amount of InsP₆ and causes an increase in InsP₅. These results are consistent with a pathway that produces InsP₆ through the sequential action of Ins(1,3,4)P₃ 5/6-kinase, Ins(1,3,4,6)P₄ 5-kinase, and Ins(1,3,4,5,6)P5 2-kinase to convert Ins(1,3,4)P₃ to InsP₆. Furthermore, the evidence implicates 5/6-kinase as the rate-limiting enzyme in this pathway.

Received for publication, October 12, 2004 , and in revised form, November 4, 2004.

^* This work was supported by National Institutes of Health Grants HL 55272, HL 16634, and H107088 and by American Heart Association Grant AHA-0475014N. 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.

These authors contributed equally to this work.

^|| To whom correspondence should be addressed: Division of Hematology, Box 8125, Washington University School of Medicine, 660 S. Euclid Ave., St. Louis, MO 63110. Tel.: 314-362-8839; Fax: 314-362-8826; E-mail: phil{at}im.wustl.edu.

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