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

Cross-linking of the Fc epsilon 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 epsilon 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 epsilon 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.