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Papers In Press, published online ahead of print July 9, 2004
J. Biol. Chem, 10.1074/jbc.M313557200
Submitted on December 11, 2003
Revised on July 9, 2004
Accepted on July 8, 2004

Involvement of smad-signaling in sphingosine 1-phosphate mediated biological responses of keratinocytes

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

Institute of Pharmacy, Berlin 14195

Corresponding Author: kleuser{at}zedat.fu-berlin.de

The lysophospholipid sphingosine 1-phosphate and the cytokine transforming growth factor beta 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 b-dependent chemotaxis of keratinocytes and mediates, in part, its growth inhibitory effect. Here we show that sphingosine 1-phosphate, independently of transforming growth factor beta -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 beta -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- and G-protein coupled-receptors.


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