Impaired Kit- but Not FcεRI-initiated Mast Cell Activation in the Absence of Phosphoinositide 3-Kinase p85α Gene Products*
- From the Departments of ‡Medicine and ¶Cell Biology, Harvard Medical School, Boston, Massachusetts 02115, the§Division of Rheumatology, Immunology and Allergy, Brigham and Women's Hospital, Boston, Massachusetts 02115, and the‖Division of Signal Transduction, Beth Israel Deaconess Medical Center, Boston, Massachusetts 02115
Abstract
The class IAphosphoinositide 3-kinases (PI3Ks) consist of a 110-kDa catalytic domain and a regulatory subunit encoded by the p85α, p85β, or p55γ genes. We have determined the effects of disrupting the p85α gene on the responses of mast cells stimulated by the cross-linking of Kit and FcεRI, receptors that reflect innate and adaptive responses, respectively. The absence of p85α gene products partially inhibited Kit ligand/stem cell factor-induced secretory granule exocytosis, proliferation, and phosphorylation of the serine/threonine kinase Akt. In contrast, p85α gene products were not required for FcεRI-initiated exocytosis and phosphorylation of Akt. LY294002, which inhibits all classes of PI3Ks, strongly suppressed Kit- and FcεRI-induced responses in p85α −/− mast cells, revealing the contribution of another PI3K family member(s). In contrast to B lymphocytes, mast cell proliferation was not dependent on Bruton's tyrosine kinase, a downstream effector of PI3K, revealing a distinct pathway of PI3K-dependent proliferation in mast cells. Our findings represent the first example of receptor-specific usage of different PI3K family members in a single cell type. In addition, because Kit- but not FcεRI-initiated signaling is associated with mast cell proliferation, the results provide evidence that distinct biologic functions signaled by these two receptors may reflect differential usage of PI3Ks.
Footnotes
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↵* This work was supported by National Institutes of Health Grants AI31599, AI41144, HL36110 (to H. R. K.), and GM41890 (to L. C. C.), fellowships from the Arthritis Foundation (to J. M. L.-K.), the Damon Runyon-Walter Winchell Cancer Research Fund, and the Leukemia Society of America (to D. A. F.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
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↵** To whom correspondence should be addressed: Smith Bldg., 6th Floor, Div. of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital, 1 Jimmy Fund Way, Boston, MA 02115. Tel.: 617-525-1307; Fax: 617-525-1308; E-mail: hrkatz@mbcrr.harvard.edu.
- Abbreviations:
- MC
-
mast cell
- KL
-
Kit ligand
- FcεRI
-
the high affinity receptor for IgE
- PI3K
-
phosphoinositide 3-kinase
- PtdIns
-
phosphatidylinositol
- Btk
-
Bruton's tyrosine kinase
- IL
-
interleukin
- mAb
-
monoclonal antibody
- FITC
-
fluorescein isothiocyanate
- BMMC
-
bone marrow-derived mast cell
- FLMC
-
fetal liver-derived mast cell
- MAR
-
F(ab′)2 mouse anti-rat IgG (heavy and light chain reactive)
- Ab
-
antibody
- Xid
-
X-linked immunodeficiency
-
- Received November 5, 1999.
- The American Society for Biochemistry and Molecular Biology, Inc.
