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J. Biol. Chem., Vol. 280, Issue 9, 7883-7889, March 4, 2005

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Acquisition of Unprecedented Phosphatidylinositol 3,5-Bisphosphate Rise in Hyperosmotically Stressed 3T3-L1 Adipocytes, Mediated by ArPIKfyve-PIKfyve Pathway^*

Diego Sbrissa and Assia Shisheva

From the Department of Physiology, Wayne State University School of Medicine, Detroit, Michigan 48201

Unlike yeast, where hyperosmotic stress induces a dramatic increase in phosphatidylinositol 3,5-bisphosphate (PtdIns 3,5-P₂) synthesis, in mammalian cells, although activating a complex array of signaling events, hyperosmotic stress fails to up-regulate PtdIns 3,5-P₂, indicating the PtdIns 3,5-P₂ pathway is not involved in mammalian osmo-protective responses. Here we report an unexpected and marked PtdIns 3,5-P₂ increase in response to hyperosmotic stress in differentiated 3T3-L1 adipocytes. Because this effect was not observed in the precursor preadipocytes, a specific role during acquisition of the adipocyte phenotype and transition into insulin-responsive cells could be suggested. However, acute insulin action did not result in a measurable PtdIns 3,5-P₂ rise, indicating the PtdIns 3,5-P₂ pathway is a specific hyperosmotically activated signaling cascade selectively operating in differentiated 3T3-L1 adipocytes. Hyperosmolarity activates different components of several kinase cascades, including p38 mitogen-activated protein and tyrosine kinases, but these appear to be separate from the activated PtdIns 3,5-P₂ pathway. Because PtdIns 3,5-P₂ is primarily produced by PIKfyve-catalyzed synthesis and requires the upstream activator hVac14 (called herein ArPIKfyve) that physically associates with and activates PIKfyve, we examined the contribution of ArPIKfyve-PIKfyve for the hyperosmotic stress-induced rise in PtdIns 3,5-P₂. Small interfering RNA-directed gene silencing to selectively deplete ArPIKfyve or PIKfyve in 3T3-L1 adipocytes determined the ArPIKfyve-PIKfyve axis fully accountable for the hyperosmotically activated PtdIns 3,5-P₂. Together these results reveal a previously uncharacterized PtdIns 3,5-P₂ pathway activated selectively in hyperosmotically stressed 3T3-L1 adipocytes and suggest a plausible role for PtdIns 3,5-P₂ in the osmo-protective response mechanism in this cell type.

Received for publication, November 10, 2004

^* This project was supported by National Institute of Health Grant DK58058 and American Diabetes Association Research Grants (to A. S.). 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.

To whom correspondence should be addressed: Dept. of Physiology, Wayne State University School of Medicine, 540 E. Canfield, Detroit, MI 48201. Tel.: 313-577-5674; Fax: 313-577-5494; E-mail: ashishev{at}med.wayne.edu.

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