Modulatory signaling motifs in B cell antigen receptor function

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DESCRIPTION (provided by applicant): B lymphocytes are responsible for the humoral immune responses to pathogens, but are also the cells involved in the production of autoantibodies in the course of autoimmune pathologies and in lymphoma formation during tumorigenesis. Development, selection, activation and differentiation of B lymphocytes depend primarily on the signal initiated by the antigen receptors, pre-BCR (on pre-B cells) and the BCR (on B cells of later developmental stages). Tyrosine phosphorylation of the BCR signal transducer elements Ig-alpha and Ig-beta is considered to be the initial event in BCR signal transduction and, thus far, is the only receptor modification studied in any depth during this event. However, in vivo studies have indicated that tyrosine phosphorylation does not recapitulate all BCR signal transduction events, and have strongly suggested that Ig-alpha (and likely Ig-beta) contains other domain(s) that modulates BCR signaling. Evidence accumulated for over a decade has suggested that Ig-alpha cytoplasmic serine and threonine amino acid residues compose a motif that modulates BCR signal transduction. Thus, we speculate that BCR serine and threonine amino acid residues are phosphorylated by, as of yet, an unidentified serine/threonine kinase(s) and this receptor modification modulates BCR signaling by regulating receptor interaction with either tyrosine kinases, phosphatases, or signal adaptors. Our aims are to definitively demonstrate BCR serine/threonine phosphorylation, to determine the kinetics of this event and to investigate the mechanism by which this protein modification modulates signaling, and influences B cell development. The studies proposed here will provide insight into novel biochemical mechanisms that regulate antigen receptor signaling in B cells, and, consequently, modulate B cell responses in vivo. These studies will provide new avenues with which to ameliorate immunodeficiencies, autoimmunities and cancer.