An essential role for RasGRP1 in mast cell function and IgE-mediated allergic response.
Cross-linking of the FcepsilonRI 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 FcepsilonRI-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 FcepsilonRI-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.
Duke Scholars
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Related Subject Headings
- Signal Transduction
- Receptors, IgE
- Phosphatidylinositol 3-Kinases
- Models, Biological
- Mice, Knockout
- Mice
- Mast Cells
- MAP Kinase Signaling System
- In Vitro Techniques
- Immunology
Citation
Published In
DOI
ISSN
Publication Date
Volume
Issue
Start / End Page
Location
Related Subject Headings
- Signal Transduction
- Receptors, IgE
- Phosphatidylinositol 3-Kinases
- Models, Biological
- Mice, Knockout
- Mice
- Mast Cells
- MAP Kinase Signaling System
- In Vitro Techniques
- Immunology