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.
Liu
Yan
Y
Department of Immunology, Duke University Medical Center, Durham, NC 27710, USA.
Zhu
Minghua
M
Nishida
Keigo
K
Hirano
Toshio
T
Zhang
Weiguo
W
D000707:Anaphylaxis / Q000209:etiology* / Q000276:immunology / Q000503:physiopathology; D000818:Animals; D015550:Cell Degranulation; D016207:Cytokines / Q000096:biosynthesis; D004789:Enzyme Activation; D020662:Guanine Nucleotide Exchange Factors / Q000172:deficiency / Q000235:genetics / Q000276:immunology / Q000502:physiology*; D007073:Immunoglobulin E / Q000378:metabolism*; D066298:In Vitro Techniques; D020935:MAP Kinase Signaling System; D008407:Mast Cells / Q000276:immunology / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008954:Models, Biological; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017455:Receptors, IgE / Q000378:metabolism; D015398:Signal Transduction
D016207:Cytokines; D020662:Guanine Nucleotide Exchange Factors; C112278:Rasgrp1 protein, mouse; D017455:Receptors, IgE; D007073:Immunoglobulin E; D019869:Phosphatidylinositol 3-Kinases