The aim of this project is to understand how Fc receptors communicate intracellular signals to initiate mast cell activation leading to inflammation. Fc receptors are key players in autoimmune diseases like systemic lupus erythematosus and in allergic disease. We have focused on signaling proteins that may serve as possible links from Fc receptor to gene expression and mast cell degranulation and on how this receptors activity is regulated. This focus is based on increaing the knowledge of potential therapeutic targets in autoimmune and allergic disease. Results: The objectives of the past year were met in the following manner. First, studies on the role of two different isoforms of Lyn kinase that associate with the IgE receptor were initiated. These studies led us to explore the two isofroms of Lyn expressed in mast cells (Lyn A and B) and to explore what their respective roles are in mast cell activation. Second, additional work explored whether other stimuli that lead to mast cell activation functioned through the use of Lyn or Fyn. Third, we also have initial findings suggesting that Fyn kinase regulates calcium influx in mast cells and this is a key event for mast cell degranulation. We also uncovered evidence for receptor heterogeniety, some associated with Fyn whereas others with Lyn. Conclusions and Significance: In summary, we found that both Fyn and Lyn kinases function is regulated in the context of other genes, as it was found that mice with differing genetic backgrounds had different kinase levels and mast cell responses were influenced by the levels of the kinases being expressed. These findings provide new avenues for future exploration toewards understanding the role of IgE Fc receptors in health and disease.

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National Institute of Arthritis and Musculoskeletal and Skin Diseases
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Falanga, Yves T; Chaimowitz, Natalia S; Charles, Nicolas et al. (2012) Lyn but not Fyn kinase controls IgG-mediated systemic anaphylaxis. J Immunol 188:4360-8
Serra-Pages, Mariona; Olivera, Ana; Torres, Rosa et al. (2012) E-prostanoid 2 receptors dampen mast cell degranulation via cAMP/PKA-mediated suppression of IgE-dependent signaling. J Leukoc Biol 92:1155-65
Furumoto, Yasuko; Charles, Nicolas; Olivera, Ana et al. (2011) PTEN deficiency in mast cells causes a mastocytosis-like proliferative disease that heightens allergic responses and vascular permeability. Blood 118:5466-75
Carmi-Levy, Irit; Motzik, Alex; Ofir-Birin, Yifat et al. (2011) Importin beta plays an essential role in the regulation of the LysRS-Ap(4)A pathway in immunologically activated mast cells. Mol Cell Biol 31:2111-21
Suzuki, Ryo; Liu, Xibao; Olivera, Ana et al. (2010) Loss of TRPC1-mediated Ca2+ influx contributes to impaired degranulation in Fyn-deficient mouse bone marrow-derived mast cells. J Leukoc Biol :
Alvarez-Errico, Damiana; Yamashita, Yumi; Suzuki, Ryo et al. (2010) Functional analysis of Lyn kinase A and B isoforms reveals redundant and distinct roles in Fc epsilon RI-dependent mast cell activation. J Immunol 184:5000-8
van der Kleij, Hanneke; Charles, Nicolas; Karimi, Khalil et al. (2010) Evidence for neuronal expression of functional Fc (epsilon and gamma) receptors. J Allergy Clin Immunol 125:757-60
Gilfillan, Alasdair M; Rivera, Juan (2009) The tyrosine kinase network regulating mast cell activation. Immunol Rev 228:149-69
Alvarez-Errico, Damiana; Lessmann, Eva; Rivera, Juan (2009) Adapters in the organization of mast cell signaling. Immunol Rev 232:195-217
Rivera, Juan; Fierro, Nora A; Olivera, Ana et al. (2008) New insights on mast cell activation via the high affinity receptor for IgE. Adv Immunol 98:85-120

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