Adaptor molecules in lymphocyte signaling

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DESCRIPTION(provided by applicant): Engagement of antigen receptors on T and B cells leads to activation of a series of signaling cascades, including phosphorylation of cellular proteins and activation of the Ras-MAPK pathway and Ca 2+ flux. In T cells, the membrane-associated adaptor molecule, LAT (Linker for activation of T cells), plays a crucial role in connecting the TCR engagement to Ras-MAPK activation and Ca 2+ flux by recruiting Grb2, Gads, and PLC-gamma-1 to the membrane. However, it is not clear how the BCR engagement is coupled to Ras-MAPK activation and Ca 2+ flux. A LAT-like molecule has not been found in B cells. Recently, we cloned a novel gene encoding a membrane-associated adaptor protein. We named this gene, LAB (Linker for activation of B cells). Our preliminary data showed that LAB shares many characteristics with LAT. We hypothesize that, in B cells, LAB functions to couple the BCR engagement to downstream Ras-MAPK activation and Ca 2+ flux by recruiting Grb2 to the membrane. This proposal aims to further study LAB function in B cell activation and development. Three specific aims are designed to test this hypothesis. In specific aim 1, LAB gene will be disrupted in the chicken DT40 B cell line. Signaling defects caused by deletion of this gene will be characterized. In specific aim 2, we will examine the functional differences between LAB and LAT using transgenic mice. In specific aim 3, LAB gene will be disrupted in mice to study LAB function in B cell development. We will also study LAB function in platelets and NK cells.