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J. Biol. Chem., Vol. 281, Issue 43, 32630-32638, October 27, 2006

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Hypertonic Stress Increases Phosphatidylinositol 4,5-Bisphosphate Levels by Activating PIP5KI^*

From the Department of Physiology, University of Texas Southwestern Medical Center, Dallas, Texas 75390

Hyperosmotic stress increases phosphoinositide levels, reorganizes the actin cytoskeleton, and induces multiple acute and adaptive physiological responses. Here we showed that phosphatidylinositol 4,5-bisphosphate (PIP₂) level increased rapidly in HeLa cells during hypertonic treatment. Depletion of the human type I phosphatidylinositol 4-phosphate 5-kinase isoform (PIP5KI) by RNA interference impaired both the PIP₂ and actin cytoskeletal responses. PIP5KI was recruited to membranes and was activated by hypertonic stress through Ser/Thr dephosphorylation. Calyculin A, a protein phosphatase 1 inhibitor, blocked the hypertonicity-induced PIP5KI dephosphorylation/activation as well as PIP₂ increase in cells. Urea, which raises osmolarity without inducing cell shrinkage, did not promote dephosphorylation nor increase PIP₂ levels. Disruption or stabilization of the actin cytoskeleton, or inhibition of the Rho kinase, did not block the PIP₂ increase nor PIP5KI dephosphorylation. Therefore, PIP5KI is dephosphorylated in a volume-dependent manner by a calyculin A-sensitive protein phosphatase, which is activated upstream of actin remodeling and independently of Rho kinase activation. Our results establish a cause-and-effect relation between PIP5KI dephosphorylation, lipid kinase activation, and PIP₂ increase in cells. This PIP₂ increase can orchestrate multiple downstream responses, including the reorganization of the actin cytoskeleton.

Received for publication, June 21, 2006 , and in revised form, August 29, 2006.

^* This work was supported in part by National Institute of General Medical Sciences Grant 5P50-GM-21681, National Institutes of Health Grant RO1 GM066110, and by the Welch Foundation (all to H. L. 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 These authors contributed equally to this work.

² Supported by the National Institutes of Health Mechanisms of Drug Action and Disposition Training Grant GM007062.

³ To whom correspondence should be addressed: Dept. of Physiology, University of Texas Southwestern Medical Center, 5323 Harry Hines Blvd., Dallas, TX 75390. Tel.: 214-645-6035; Fax: 214-645-6039; E-mail: helen.yin{at}utsouthwestern.edu.

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