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J. Biol. Chem., Vol. 278, Issue 29, 27088-27095, July 18, 2003

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Involvement of Integrins in Osmosensing and Signaling toward Autophagic Proteolysis in Rat Liver^*

Stephan vom Dahl , Freimut Schliess, Regina Reissmann, Boris Görg, Oliver Weiergräber, Mariana Kocalkova , Frank Dombrowski  and Dieter Häussinger

From the Division of Gastroenterology, Hepatology and Infectious Diseases, Heinrich-Heine-University, Moorenstrasse 5, D-40225-Düsseldorf, Germany and the Institute of Pathology, Otto-von-Guericke-University, D-40225 Magdeburg, Germany

Inhibition of autophagic proteolysis by hypoosmotic or amino acid-induced hepatocyte swelling requires osmosignaling toward p38^MAPK; however, the upstream osmosensing and signaling events are unknown. These were studied in the intact perfused rat liver with a preserved in situ environment of hepatocytes. It was found that hypoosmotic hepatocyte swelling led to an activation of Src (but not FAK), Erks, and p38^MAPK, which was prevented by the integrin inhibitory hexapeptide GRGDSP, but not its inactive analogue GRGESP. Src inhibition by PP-2 prevented hypoosmotic MAP kinase activation, indicating that the integrin/Src system is located upstream in the osmosignaling toward p38^MAPK and Erks. Inhibition of the integrin/Src system by the RGD motif-containing peptide or PP-2 also prevented the inhibition of proteolysis and the decrease in autophagic vacuole volume, which is otherwise observed in response to hypoosmotic or glutamine/glycine-induced hepatocyte swelling. These inhibitors, however, did not affect swelling-independent proteolysis inhibition by phenylalanine. In line with a role of p38^MAPK in triggering the volume regulatory decrease (RVD), PP-2 and the RGD peptide blunted RVD in response to hypoosmotic cell swelling. The data identify integrins and Src as upstream events in the osmosignaling toward MAP kinases, proteolysis, and RVD. They further point to a role of integrins as osmo- and mechanosensors in the intact liver, which may provide a link between cell volume and cell function.

Received for publication, October 18, 2002 , and in revised form, March 26, 2003.

^* This work was supported by Grant SFB 575 from the Deutsche Forschungsgemeinschaft (DFG). 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: Division of Gastroenterology, Hepatology, and Infectious Diseases, Heinrich-Heine-University, Moorenstr. 5, D-40225 Düsseldorf, Germany. Tel.: 0049-211-811-8764; Fax: 0049-211-811-8752; E-mail: dahlv{at}uni-duesseldorf.de.

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