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J. Biol. Chem., Vol. 279, Issue 37, 38471-38479, September 10, 2004

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Involvement of Smad Signaling in Sphingosine 1-Phosphate-mediated Biological Responses of Keratinocytes^*

Bettina Sauer, Rüdiger Vogler, Henrik von Wenckstern, Makiko Fujii¶, Mario B. Anzano¶, Adam B. Glick||, Monika Schäfer-Korting, Anita B. Roberts¶, and Burkhard Kleuser**

From the Institute of Pharmacy, Pharmacology and Toxicology, Free University Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany and the ^¶Laboratory of Cell Regulation and Carcinogenesis and ^||Laboratory of Cellular Carcinogenesis and Tumor Promotion, NCI, National Institutes of Health, Bethesda, Maryland 20892

The lysophospholipid sphingosine 1-phosphate and the cytokine-transforming growth factor are both released from degranulating platelets at wound sites, suggesting a broad spectrum of effects involved in wound healing. Interestingly, both of these molecules have been previously shown to induce chemotaxis but to strongly inhibit the growth of keratinocytes, while stimulating the proliferation of fibroblasts. In contrast to sphingosine 1-phosphate, the signaling cascade of the growth factor has been extensively examined. Specifically, Smad3 has been shown to be an essential mediator of transforming growth factor -dependent chemotaxis of keratinocytes and mediates, in part, its growth-inhibitory effect. Here we show that sphingosine 1-phosphate, independently of transforming growth factor secretion, induces a rapid phosphorylation of Smad3 on its C-terminal serine motif and induces its partnering with Smad4 and the translocation of the complex into the nucleus. Moreover, sphingosine 1-phosphate fails to induce chemotaxis or inhibit the growth of Smad3-deficient keratinocytes, suggesting that Smad3 plays an unexpected functional role as a new target in sphingosine 1-phosphate signaling. Both sphingosine 1-phosphate receptors and the transforming growth factor -type I receptor serine/threonine kinase are essential for activation of Smad3 by this lysophospholipid and the dependent biological responses, indicating a novel cross-talk between serine/threonine kinase receptors and G-protein coupled receptors.

Received for publication, December 11, 2003 , and in revised form, June 21, 2004.

^* This work was supported by Deutsche Forschungsgemeinschaft Grant Kl 988 3/1, FG 463. 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.

Recipient of a fellowship from the Berliner Graduiertenförderung.

^** To whom correspondence should be addressed: Institute of Pharmacy, Pharmacology, and Toxicology, Free University Berlin, Königin-Luise-Str. 2+4, D-14195 Berlin, Germany. Tel.: 49-30-838-54561; Fax: 49-30-838-54399; E-mail: kleuser{at}zedat.fu-berlin.de.

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