B lymphocytes express cell surface antigen receptors (BCR) that transduce signals leading to a variety of responses including apoptosis, anergy, receptor editing, priming for T-B collaboration and proliferation, depending upon antigen structure and differentiative stage of responding cells. The molecular mechanisms underlying this decision making process, while undefined, presumably operate at the level of the receptor. BCR are composed of membrane immunoglobulin and noncovalently associated Ig-alpha and Ig-beta heterodimers. Surprisingly, recent findings indicate that Ia molecules expressed on antigen primed B cells also associate with Ig-alpha/Ig-beta dimers. Ig-alpha and Ig-beta each contain one copy of an ~26 amino acid sequence motif, termed ITAM, that forms the receptor's functional and physical interface with molecular effectors of signal transduction. ITAMs each contain two conserved tyrosine residues that play critical roles in signal transduction and are variably phosphorylated upon receptor ligation. Phosphorylated ITAMs appear to function as a organizing lattice that binds and in some cases activates effectors. The investigator hypothesizes that differential phosphorylation of ITAM tyrosines serves to integrate the """"""""quality"""""""" of antigenic signals, mediating their induction of distinct biologic responses. Receptor context (Ia vs Ig) may also affect receptor phosphorylation. He further hypothesizes that cell developmental stage modifies signal integration by virtue of differential expression of kinases that phosphorylate ITAMs. The proposed studies will address the possibility that tyrosine specificity of ligand induced ITAM phosphorylation is determined by: 1) the Ia vs Ig context of the ITAM, 2) the differentiative stage of the responding cell and 3) the quality of signal. They will further define the functional consequences of specific ITAM phosphorylation events. Finally, they will define Ia structural requirements for association with Ig-alpha/Ig-beta on antigen primed B cells. This will allow in vivo analysis of the physiologic function of this interaction. Studies will involve cell biologic and biochemical analysis of signal transduction in immunoglobulin transgenic mouse B cells and genetically manipulated B lymphoma cells. Results should provide important new insights regarding the molecular basis of immunodeficiency, autoimmunity and aging.
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