Mast cell activation plays a critical pathophysiologic role in asthma and allergy. A role for mast cell activation has also been described in multiple sclerosis, rheumatoid arthritis and coronary artery disease. However, recent studies challenge the dogma of a pathological role for mast cell activation, demonstrating its prominent role in the early phases of innate immunity to pathogenic bacteria. These observations make our understanding of mast cell biology more crucial than ever. While several cytokines influence the growth, survival, and maturation of mast cells, stem cell factor (SCF) and its interaction via the tyrosine kinase receptor, c-Kit is essential for normal mast cell development and function. Mice deficient in the expression of c-Kit lack mast cells and exhibit enhanced mortality to induced bacterial infections. Thus, although an important role for c-Kit and IgE receptor initiated signals in regulating normal development and function of mast cells has been demonstrated, the signaling pathways downstream from these receptors that regulate these processes are poorly understood. Identification of key intracellular signaling molecules and pathways involved in regulating the development and function of mast cells via these receptors will facilitate the design of specific molecular therapies for the treatment of mast cell disorders, including human mastocytosis associated with gain-of-function mutations of c-Kit, chronic inflammation, allergy as well as for promoting immunity to bacterial infections. Our long-range goal is to understand the signaling mechanism(s) that control mast cell functions downstream from cytokine receptors as well as immunoreceptors. The objective of this application is to determine how SHIP phosphatase, Lyn Src family kinase and p85 regulatory subunits (a and b) of class IA PI-3Kinase interact to regulate mast cell differentiation, growth/survival as well as cytokine production and degranulation. The central hypothesis of this application, which has been formulated on the basis of our preliminary data, is that Lyn kinase is critical for the activation of SHIP phosphatase in mast cells. In the absence of SHIP phosphorylation (due to lack of Lyn expression) mast cells demonstrate hypersensitivity to SCF-induced survival, growth and differentiation as well as enhanced IgE receptor induced degranulation and cytokine production. These phenotypes are due to hyperactivation of the PI-3Kinase/Akt pathway. Furthermore, p85ct and p85|3 regulatory subunits of class IA PI-3Kinase play quantitatively distinct roles in regulating mast cell functions. These differences are due to the presence of unique amino terminal sequences in p85a vs (p85|3). Our proposed studies will provide unique insights into the physiologic significance of the in vivo interactions between SHIP, Lyn and p85 regulatory subunits of class IA PI-3Kinase in regulating all aspects of mast cell biology. ? ? ?
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