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; 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，但也是在自身免疫性病理学和肿瘤发生过程中淋巴瘤形成的自身抗体产生的细胞。 B淋巴细胞的开发，选择，激活和分化主要取决于抗原受体，PRE-BCR（在PR​​E-B细胞上）和BCR（在后期发育阶段的B细胞上）引发的信号。 BCR信号传感器元件Ig-Alpha和Ig-beta的酪氨酸磷酸化被认为是BCR信号转导中的初始事件，到目前为止，这是此事件中任何深度研究的唯一受体修饰。然而，体内研究表明，酪氨酸磷酸化并未概括所有BCR信号转导事件，并强烈建议Ig-Alpha（以及可能的Ig-beta）包含调节BCR信号的其他域。积累了十多年的证据表明，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丝氨酸和苏氨酸氨基酸残基被未鉴定的丝氨酸/苏氨酸激酶磷酸化，并且该受体修饰通过调节受体与酪氨酸激酶，磷酸酶，磷酸酶，信号适配器的受体相互作用来调节BCR信号传导。我们的目的是确定证明BCR丝氨酸/苏氨酸磷酸化，以确定此事件的动力学并研究该蛋白质修饰调节信号并影响B细胞发育的机制。这里提出的研究将提供对调节B细胞中抗原受体信号传导的新型生化机制的见解，因此，在体内调节B细胞反应。这些研究将提供新的途径，以减轻免疫缺陷，自身免疫和癌症。