Modulatory signaling motifs in B cell antigen receptor

描述（由申请人提供）：B淋巴细胞负责对病原体的体液免疫反应，但在自身免疫病理过程中也是参与自身抗体产生的细胞，在肿瘤发生过程中也参与淋巴瘤形成。B淋巴细胞的发育、选择、激活和分化主要取决于抗原受体、前BCR（对前B细胞）和BCR（对发育后期的B细胞）发起的信号。酪氨酸磷酸化BCR信号转导元件ig - α和ig - β被认为是BCR信号转导的初始事件，也是迄今为止在该事件中唯一深入研究的受体修饰。然而，体内研究表明酪氨酸磷酸化并不能概括所有BCR信号转导事件，并强烈表明igg - α（可能还有igg - β）包含其他调节BCR信号传导的结构域。十多年来积累的证据表明，igg - α细胞质丝氨酸和苏氨酸氨基酸残基组成了一个调节BCR信号转导的基序。因此，我们推测BCR丝氨酸和苏氨酸氨基酸残基被一种尚未确定的丝氨酸/苏氨酸激酶磷酸化，这种受体修饰通过调节受体与酪氨酸激酶、磷酸酶或信号接头的相互作用来调节BCR信号。我们的目标是明确地证明BCR丝氨酸/苏氨酸磷酸化，确定这一事件的动力学，并研究这种蛋白质修饰调节信号传导和影响B细胞发育的机制。本文提出的研究将提供新的生化机制，以调节B细胞中的抗原受体信号，从而调节B细胞在体内的反应。这些研究将为改善免疫缺陷、自身免疫和癌症提供新的途径。

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.