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Molecular and Cellular Biology, October 2004, p. 8765-8777, Vol. 24, No. 19
0270-7306/04/$08.00+0     DOI: 10.1128/MCB.24.19.8765-8777.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Early Activation of Sphingosine Kinase in Mast Cells and Recruitment to Fc{varepsilon}RI Are Mediated by Its Interaction with Lyn Kinase

Nicole Urtz,1 Ana Olivera,2 Elisa Bofill-Cardona,1 Robert Csonga,1 Andreas Billich,1 Diana Mechtcheriakova,1 Frederic Bornancin,1 Max Woisetschläger,1 Juan Rivera,2 and Thomas Baumruker1*

Novartis Institute for Biomedical Research Vienna, Vienna, Austria,1 Molecular Immunology and Inflammation Branch, National Institutes of Health, Bethesda, Maryland2

Received 28 January 2004/ Returned for modification 1 April 2004/ Accepted 6 July 2004

Sphingosine kinase has been recognized as an essential signaling molecule that mediates the intracellular conversion of sphingosine to sphingosine-1-phosphate. In mast cells, induction of sphingosine kinase and generation of sphingosine-1-phosphate have been linked to the initial rise in Ca2+, released from internal stores, and to degranulation. These events either precede or are concomitant with the activation of phospholipase C-{gamma} and the generation of inositol trisphosphate. Here we show that sphingosine kinase type 1 (SPHK1) interacts directly with the tyrosine kinase Lyn and that this interaction leads to the recruitment of this lipid kinase to the high-affinity receptor for immunoglobulin E (Fc{varepsilon}RI). The interaction of SPHK1 with Lyn caused enhanced lipid and tyrosine kinase activity. After Fc{varepsilon}RI triggering, enhanced sphingosine kinase activity was associated with Fc{varepsilon}RI in sphingolipid-enriched rafts of mast cells. Bone marrow-derived mast cells from Lyn–/– mice, compared to syngeneic wild-type cells, were defective in the initial induction of SPHK1 activity, and the defect was overcome by retroviral Lyn expression. These findings position the activation of SPHK1 as an Fc{varepsilon}RI proximal event.

* Corresponding author. Mailing address: Novartis Institute for Biomedical Research, Brunner Strasse 59, A-1235 Vienna, Austria. Phone: 43 1 86634 527. Fax: 43 1 86634 582. E-mail: thomas.baumruker{at}pharma.novartis.com.

Molecular and Cellular Biology, October 2004, p. 8765-8777, Vol. 24, No. 19
0022-538X/04/$08.00+0     DOI: 10.1128/MCB.24.19.8765-8777.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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