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| Structure and function of MS4A proteins | |||||||||||||
Mast cells play a significant role in the pathophysiology of asthma, allergy, and many other diverse diseases including pulmonary fibrosis and rheumatoid disease. Allergens and other non-immunological stimuli activate complex signaling cascades in mast cells that lead to the secretion of a plethora of autacoid mediators, cytokines and proteases. An influx of extracellular Ca2+ is an essential requirement for the release of many of these factors. Recently a new family of 4 membrane-spanning proteins has been identified and implicated in the regulation of Ca2+ influx. This MS4A family consists of at least 13 members. All have 4 transmembrane domains with cytoplasmic N- and C-termini and their expression is largely confined to immunological cells. Little is known about their function, with only MS4A1 and MS4A2 having been studied to any degree. MS4A1, also known as CD20, is an integral part of the B cell receptor and is involved in cell cycle progression and signal transduction. MS4A2 forms part of the high affinity IgE receptor. Work in our laboratory has identified several members of this family in human lung mast cells (MS4A2, 4, 6 and 7) including several novel splice variants of unknown function. This project will investigate MS4A structure, assembly and interaction with other signalling proteins in mast cells. In particular, we will investigate the formation of homo/heteromultimers of MS4A proteins and identify regions important for assembly, examine the role of the novel splice variants in MS4A trafficking, and determine whether MS4A proteins other than MS4A2 interact with the high affinity IgE receptor. We also have preliminary evidence that MS4A4 interacts with the KCa3.1 K+ channel which will be explored further. The project will provide experience in a range of molecular biology, cell biology and protein techniques. The position will be co-supervised by Professor Peter Bradding (Department of Infection, Immunity and Inflammation, University of Leicester) who has a long-standing collaboration with Dr Leyland, and who is an internationally recognised expert in mast cell biology. Liang and Tedder (2001) Genomics 72, 119-127 Li et al (2003) J Biol Chem 278, 42427-42434 |
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