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J. Biol. Chem., Vol. 280, Issue 27, 25548-25557, July 8, 2005

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Src Regulates Distinct Pathways for Cell Volume Control through Vav and Phospholipase C^*

Elisabeth T. Barfod, Ann L. Moore, Richard F. Melnick, and Steven D. Lidofsky¶

From the Departments of Medicine and Pharmacology, University of Vermont, Burlington, Vermont 05405

Cell volume recovery in response to swelling requires reorganization of the cytoskeleton and fluid efflux. We have previously shown that electrolyte and fluid efflux via K⁺ and Cl^– channels is controlled by swelling-induced activation of phospholipase C (PLC). Recently, integrin engagement has been suggested to trigger responses to swelling through activation of Rho family GTPases and Src kinases. Because both PLC and Rho GTPases can be regulated by Src during integrin-mediated cytoskeletal reorganization, we sought to identify swelling-induced Src effectors. Upon hypotonic challenge, Src was rapidly activated in transient plasma membrane protrusions, where it colocalized with Vav, an activator of Rho GTPases. Inhibition of Src with PP2 attenuated phosphorylation of Vav. PP2 also attenuated phosphorylation of PLC, and inhibited swelling-mediated activation of K⁺ and Cl^– channels and cell volume recovery. These findings suggest that swelling-induced Src regulates cytoskeletal dynamics, through Vav, and fluid efflux, through PLC, and thus can coordinate structural reorganization with fluid balance to maintain cellular integrity.

Received for publication, October 14, 2004 , and in revised form, March 23, 2005.

^* This work was supported in part by National Institutes of Health Grant DK56644 (to S. D. L.). Use of the DeltaVision restoration microscope and Volocity 3 software was provided through the Imaging Core supported by National Institutes of Health Grant P20 RR16435 from the Center of Biomedical Research Excellence program of the National Center for Research Resources. 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 Figs. S1 and S2 and a video.

^¶ To whom correspondence should be addressed: Burgess 414 MFU, University of Vermont, Burlington, VT 05401. Tel.: 802-847-5990; Fax: 802-847-4928; E-mail: steven.lidofsky{at}uvm.edu.

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