The Journal of Experimental Medicine
Cytokines in immune regulation
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Published online December 26, 2006
doi:10.1084/jem.20061598
The Journal of Experimental Medicine, Vol. 204, No. 1, 93-103
The Rockefeller University Press, 0022-1007 $30.00
© 2006 Liu et al.
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ARTICLE

 An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response

Yan Liu1, Minghua Zhu1, Keigo Nishida2, Toshio Hirano2, and Weiguo Zhang1

1 Department of Immunology, Duke University Medical Center, Durham, NC 27710
2 Laboratory for Cytokine Signaling, RIKEN Research Center for Allergy and Immunology, Kanagawa 230-0045, Japan

CORRESPONDENCE Weiguo Zhang: zhang033{at}mc.duke.edu

Cross-linking of the Fc{varepsilon}RI activates the phosphatidyl inositol 3 kinase (PI3K) and mitogen-activated protein kinase pathways. Previous studies demonstrate that Ras guanyl nucleotide-releasing protein (RasGRP)1 is essential in T cell receptor–mediated Ras-Erk activation. Here, we report that RasGRP1 plays an important role in Fc{varepsilon}RI-mediated PI3K activation and mast cell function. RasGRP1-deficient mice failed to mount anaphylactic allergic reactions. RasGRP1–/– mast cells had markedly reduced degranulation and cytokine production. Although Fc{varepsilon}RI-mediated Erk activation was normal, PI3K activation was diminished. Consequently, activation of Akt, PIP3-dependent kinase, and protein kinase C {delta} was defective. Expression of a constitutively active form of N-Ras could rescue the degranulation defect and Akt activation. We further demonstrated that RasGRP1–/– mast cells were defective in granule translocation, microtubule formation, and RhoA activation. Our results identified RasGRP1 as an essential regulator of mast cell function.

Abbreviations used: BMMC, bone marrow–derived mast cell; DAG, diacylglycerol; GEF, guanine-nucleotide exchange factor; LAT, linker for activation of T cells; MAPK, mitogen-activated protein kinase; PDK1, phosphatidyl inositol-3,4,5-triphosphate–dependent kinase 1; PI3K, phosphatidyl inositol 3 kinase; PIP3, phosphatidyl inositol-3,4,5-triphosphate; PKC, protein kinase C; PLC, phospholipase C; RasGRP, Ras guanyl nucleotide-releasing protein; RBD, Ras-binding domain; SCF, stem cell factor.


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