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

The lysophospholipid sphingosine 1-phosphate and the cytokine-transforming growth factor β 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 chem...

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Bibliographic Details
Published in:The Journal of biological chemistry 2004-09, Vol.279 (37), p.38471-38479
Main Authors: Sauer, Bettina, Vogler, Rüdiger, von Wenckstern, Henrik, Fujii, Makiko, Anzano, Mario B., Glick, Adam B., Schäfer-Korting, Monika, Roberts, Anita B., Kleuser, Burkhard
Format: Article
Language:English
Subjects:
Amino Acid Motifs
Animals
Biotinylation
Blood Platelets - metabolism
Blotting, Western
Cell Division
Cell Line
Cell Movement
Cell Nucleus - metabolism
Chemotaxis
Dimerization
DNA - chemistry
DNA - metabolism
DNA-Binding Proteins - metabolism
Fibroblasts - metabolism
Gene Deletion
Humans
Keratinocytes - metabolism
Lysophospholipids - metabolism
Mice
Mice, Inbred C57BL
Oligonucleotides, Antisense - chemistry
Phosphorylation
Precipitin Tests
Promoter Regions, Genetic
Protein Binding
Protein Transport
Signal Transduction
Smad3 Protein
Smad4 Protein
Sphingosine - analogs & derivatives
Sphingosine - metabolism
Time Factors
Trans-Activators - metabolism
Transforming Growth Factor beta - metabolism
Wound Healing
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Summary:The lysophospholipid sphingosine 1-phosphate and the cytokine-transforming growth factor β 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 β-dependent chemotaxis of keratinocytes and mediates, in part, its growth-inhibitory effect. Here we show that sphingosine 1-phosphate, independently of transforming growth factor β 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 β-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.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M313557200