title: Involvement of Smad signaling in sphingosine 1-phosphate-mediated biological responses of keratinocytes.
abstract: 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 beta-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 receptors and G-protein coupled receptors.
authors.affiliation: Institute of Pharmacy, Pharmacology and Toxicology, Free University Berlin, Königin-Luise-Strasse 2+4, D-14195 Berlin, Germany.
authors.forename: Bettina
authors.initials: B
authors.lastname: Sauer
authors.forename: Rüdiger
authors.initials: R
authors.lastname: Vogler
authors.forename: Henrik
authors.initials: H
authors.lastname: von Wenckstern
authors.forename: Makiko
authors.initials: M
authors.lastname: Fujii
authors.forename: Mario B
authors.initials: MB
authors.lastname: Anzano
authors.forename: Adam B
authors.initials: AB
authors.lastname: Glick
authors.forename: Monika
authors.initials: M
authors.lastname: Schäfer-Korting
authors.forename: Anita B
authors.initials: AB
authors.lastname: Roberts
authors.forename: Burkhard
authors.initials: B
authors.lastname: Kleuser
mesh_terms: D020816:Amino Acid Motifs; D000818:Animals; D019921:Biotinylation; D001792:Blood Platelets / Q000378:metabolism; D015153:Blotting, Western; D002455:Cell Division; D002460:Cell Line; D002465:Cell Movement; D002467:Cell Nucleus / Q000378:metabolism; D002633:Chemotaxis; D004247:DNA / Q000737:chemistry / Q000378:metabolism; D004268:DNA-Binding Proteins / Q000378:metabolism*; D019281:Dimerization; D005347:Fibroblasts / Q000378:metabolism; D017353:Gene Deletion; D006801:Humans; D015603:Keratinocytes / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D016376:Oligonucleotides, Antisense / Q000737:chemistry; D010766:Phosphorylation; D011233:Precipitin Tests; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D021381:Protein Transport; D015398:Signal Transduction; D051900:Smad3 Protein; D051901:Smad4 Protein; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism*; D013997:Time Factors; D015534:Trans-Activators / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014945:Wound Healing
chemical_list: D004268:DNA-Binding Proteins; D008246:Lysophospholipids; D016376:Oligonucleotides, Antisense; C497790:SMAD3 protein, human; C497796:SMAD4 protein, human; D051900:Smad3 Protein; C497791:Smad3 protein, mouse; D051901:Smad4 Protein; C490810:Smad4 protein, mouse; D015534:Trans-Activators; D016212:Transforming Growth Factor beta; C060506:sphingosine 1-phosphate; D004247:DNA; D013110:Sphingosine