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J. Biol. Chem., Vol. 281, Issue 5, 2515-2525, February 3, 2006
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IgE-dependent Activation of Sphingosine Kinases 1 and 2 and Secretion of Sphingosine 1-Phosphate Requires Fyn Kinase and Contributes to Mast Cell Responses*
1
224
From the
Molecular Inflammation Section, Molecular Immunology and Inflammation Branch, NIAMS, ¶Genetics of Development and Disease Branch, NIDDK, and ||Laboratory of Allergic Diseases, NIAID, National Institutes of Health, Bethesda, Maryland 20892, Novartis Institute for BioMedical Research/Vienna, 59 Brunner Strasse, Vienna A-1235, Austria, and the **Cancer Biology Program, Division of Hematology and Oncology, Beth Israel Deaconess Medical Center and Harvard Medical School, Boston, Massachusetts 02215
Engagement of the high affinity receptor for IgE (Fc
RI) on mast cells results in the production and secretion of sphingosine 1-phosphate (S1P), a lipid metabolite present in the lungs of allergen-challenged asthmatics. Herein we report that two isoforms of sphingosine kinase (SphK1 and SphK2) are expressed and activated upon FcRI engagement of bone marrow-derived mast cells (BMMC). Fyn kinase is required for FcRI coupling to SphK1 and -2 and for subsequent S1P production. Normal activation of SphK1 and -2 was restored by expression of wild type Fyn but only partly with a kinase-defective Fyn, indicating that induction of SphK1 and SphK2 depended on both catalytic and noncatalytic properties of Fyn. Downstream of Fyn, the requirements for SphK1 activation differed from that of SphK2. Whereas SphK1 was considerably dependent on the adapter Grb2-associated binder 2 and phosphatidylinositol 3-OH kinase, SphK2 showed minimal dependence on these molecules. Fyn-deficient BMMC were defective in chemotaxis and, as previously reported, in degranulation. These functional responses were partly reconstituted by the addition of exogenous S1P to FcRI-stimulated cells. Taken together with our previous study, which demonstrated delayed SphK activation in Lyn-deficient BMMC, we propose a cooperative role between Fyn and Lyn kinases in the activation of SphKs, which contributes to mast cell responses.
Received for publication, August 12, 2005 , and in revised form, November 23, 2005.
* This work was supported in part by NIAMS, National Institutes of Health (NIH) (to A. O. and J. R.) and NIDDK, NIH (to K. M. and R. L. P.) and by United States-Israel Binational Science Foundation Grant 2000016 (to J. R.). 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.
The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. 1.
2 Supported by the Novartis Research Institute Vienna.
3 Supported by NIH Grant AI51612.
1 To whom correspondence may be addressed: NIAMS, National Institutes of Health, Bldg. 10, Rm. 9N228, Bethesda, MD 20892-1820. Tel.: 301-496-7592; Fax: 301-480-1580; E-mail: oliveraa{at}mail.nih.gov. 4To whom correspondence may be addressed: NIAMS, National Institutes of Health, Bldg. 10, Rm. 9N228, Bethesda, MD 20892-1820. Tel.: 301-496-7592; Fax: 301-480-1580; E-mail: juan_rivera{at}nih.gov.
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