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J. Biol. Chem., Vol. 282, Issue 42, 30754-30762, October 19, 2007

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Cloning and Characterization of Two Human VIP1-like Inositol Hexakisphosphate and Diphosphoinositol Pentakisphosphate Kinases^*

From the Departments of Pharmacology and Cancer Biology and of Biochemistry, Howard Hughes Medical Institute, Duke University Medical Center, Durham, North Carolina, 27710

Eukaryotes possess numerous inositol phosphate (IP) and diphosphoinositol phosphate (PP-IPs or inositol pyrophosphates) species that act as chemical codes important for intracellular signaling pathways. Production of IP and PP-IP molecules occurs through several classes of evolutionarily conserved inositol phosphate kinases. Here we report the characterization of a human inositol hexakisphosphate (IP₆) and diphosphoinositol pentakisphosphate (PP-IP₅ or IP₇) kinase with similarity to the yeast enzyme Vip1, a recently identified IP₆/IP₇ kinase (Mulugu, S., Bai, W., Fridy, P. C., Bastidas, R. J., Otto, J. C., Dollins, D. E., Haystead, T. A., Ribeiro, A. A., and York, J. D. (2007) Science 316, 106–109). Recombinant human VIP1 exhibits in vitro IP₆ and IP₇ kinase activities and restores IP₇ synthesis when expressed in mutant yeast. Expression of human VIP1 in HEK293T cells engineered to produce high levels of IP₇ results in dramatic increases in bisdiphosphoinositol tetrakisphosphate (PP₂-IP₄ or IP₈). Northern blot analysis indicates that human VIP1 is expressed in a variety of tissues and is enriched in skeletal muscle, heart, and brain. The subcellular distribution of tagged human VIP1 is indicative of a cytoplasmic non-membrane localization pattern. We also characterized human and mouse VIP2, an additional gene product with nearly 90% similarity to VIP1 in the kinase domain, and observed both IP₆ and IP₇ kinase activities. Our data demonstrate that human VIP1 and VIP2 function as IP₆ and IP₇ kinases that act along with the IP6K/Kcs1-class of kinases to convert IP₆ to IP₈ in mammalian cells, a process that has been found to occur in response to various stimuli and signaling events.

Received for publication, June 6, 2007 , and in revised form, July 23, 2007.

^* This work was supported by a grant from the Howard Hughes Medical Institute (to J. D. Y.) and National Institutes of Health Grants R01 HL-55672 and R33 DK070272 (to J. D. Y.). 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: Duke University Medical Center, DUMC Box 3813, Duke University Medical Center, Durham, NC 27710. Tel.: 919-681-6414; Fax: 919-668-0991; E-mail: yorkj{at}duke.edu.

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