Bimp3 in Antigen Receptor Signaling and MALT Lymphoma

Bimp3 在抗原受体信号转导和 MALT 淋巴瘤中的作用

• 批准号: 7106500
• 负责人: LINDA M MCALLISTER-LUCAS
• 金额: $ 13.37万
• 依托单位: UNIVERSITY OF MICHIGAN AT ANN ARBOR
• 依托单位国家: 美国
• 财政年份: 2003
• 资助国家: 美国
• 起止时间: 2003-08-25 至 2008-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7106500
• 关键词: B cell receptor; B lymphocyte; BCL2 gene /protein; SDS polyacrylamide gel electrophoresis; T cell receptor; antigen receptors; biological signal transduction; gel mobility shift assay; genetically modified animals; guanosine monophosphate; immunoprecipitation; laboratory mouse; leukocyte activation /transformation; lymphoma; membrane proteins; neoplastic transformation; nuclear factor kappa beta; protein kinase; protein protein interaction; protein structure function; receptor expression; secretory immune system; tissue support frame

DESCRIPTION (provided by applicant): The Bimps (BcI10 Interacting MAGUK Proteins) are a newly described family of signaling proteins that activate the pro-survival transcription factor, NF-kappaB. Bimps belong to the larger MAGUK (Membrane Associated Guanylate Kinase) family, a class of proteins composed of multiple distinct protein/protein interaction domains that function as molecular scaffolds in assembling multiprotein complexes at the plasma membrane. Bimps bind to and operate upstream of Bcl10, an NF-kappaB signaling molecule that is known to be an essential mediator of lymphocyte proliferation in response to antigen. The genes encoding Bcl10 and its downstream binding partner, MALT1, are each targets of recurrent chromosomal translocation in mucosa associated lymphoid tissue (MALT) lymphoma, suggesting that perturbation of the Bcl10-mediated NF-kappaB signaling pathway can promote lymphomatous transformation. Our preliminary data suggest that the Bimp proteins function to link surface receptor signaling and subsequent protein kinase C (PKC) activation to Bcl10-mediated induction of NF-(B. We hypothesize that the lymphocyte specific Bimp isoform, Bimp3, functions as a scaffold to assemble the signaling molecules that are required for Bcl10/MALT1-mediated NF-(B activation in response to lymphocyte antigen receptor stimulation. Furthermore, we hypothesize that disruption of the normal mechanisms by which the antigen receptor and Bimp3 regulate Bcl10 and MALT1 activity, as a consequence of chromosomal translocation, contributes to the pathogenesis of MALT lymphoma. In order to test these hypotheses, we propose three specific aims: 1) Determine if Bimp3, Bcl10 and MALT1 participate in a common NF-(B signaling pathway in lymphocytes with known antigen receptor-related signaling molecules; 2) Delineate the function of the individual protein/protein interaction domains within the Bimp3 structure, and 3) Characterize the physiological role of Bimp3 by generating and analyzing mice deficient in Bimp3. The career development program outlined in this proposal will build upon the investigator's prior research experience and will also provide the opportunity to master new laboratory techniques, to interact with a new mentor and team of collaborators, and to participate in additional didactic training in immunology, mouse genetics and bioinformatics. This training experience will ultimately lead to transition to the status of independent investigator.

描述（由申请人提供）：Bimps （BcI10相互作用的MAGUK蛋白）是一个新发现的信号蛋白家族，可激活促生存转录因子NF-kappaB。Bimps属于较大的MAGUK（膜相关鸟苷酸激酶）家族，这是一类由多个不同的蛋白/蛋白相互作用结构域组成的蛋白质，在质膜上组装多蛋白复合物时起分子支架的作用。Bcl10是一种NF-kappaB信号分子，已知是淋巴细胞对抗原反应增殖的重要介质。编码Bcl10及其下游结合伙伴MALT1的基因都是粘膜相关淋巴组织（MALT）淋巴瘤复发性染色体易位的靶点，这表明干扰Bcl10介导的NF-kappaB信号通路可促进淋巴瘤转化。