Modulatory signaling motifs in B cell antigen receptor

B 细胞抗原受体中的调节信号基序

• 批准号: 6982873
• 负责人: Roberta Pelanda
• 金额: $ 19.5万
• 依托单位: NATIONAL JEWISH HEALTH
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-07-01 至 2007-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6982873
• 关键词: B cell receptor; B lymphocyte; CD antigens; antibody; biological signal transduction; genetically modified animals; humoral immunity; immunoglobulins; immunologic receptors; laboratory mouse; phosphorylation; protein protein interaction; protein structure function; receptor binding; receptor expression; serine; serine threonine protein kinase; threonine; tyrosine

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.

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，但也是参与自身免疫病理过程中自身抗体产生以及肿瘤发生过程中淋巴瘤形成的细胞。 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（在前 B 细胞上）和 BCR（在后期发育阶段的 B 细胞上）引发的信号。 BCR 信号转导元件 Ig-α 和 Ig-β 的酪氨酸磷酸化被认为是 BCR 信号转导中的初始事件，并且是迄今为止在该事件期间任何深度研究的唯一受体修饰。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 Ig-α（以及可能的 Ig-β）包含调节 BCR 信号传导的其他结构域。十多年来积累的证据表明，Ig-α 细胞质丝氨酸和苏氨酸氨基酸残基组成了调节 BCR 信号转导的基序。因此，我们推测 BCR 丝氨酸和苏氨酸残基被一种尚未鉴定的丝氨酸/苏氨酸激酶磷酸化，并且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 信号传导。我们的目标是明确证明 BCR 丝氨酸/苏氨酸磷酸化，确定该事件的动力学，并研究该蛋白质修饰调节信号传导和影响 B 细胞发育的机制。这里提出的研究将深入了解调节 B 细胞中抗原受体信号传导的新生化机制，从而调节体内 B 细胞反应。这些研究将为改善免疫缺陷、自身免疫和癌症提供新途径。