Regulation of CARD11 signaling in normal and dysregulated lymphocyte development

CARD11 信号在正常和失调淋巴细胞发育中的调节

• 批准号: 8829795
• 负责人: Joel L Pomerantz
• 金额: $ 33.62万
• 依托单位: JOHNS HOPKINS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-07-19 至 2016-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829795
• 关键词: Affect; Alleles; Antigen Receptors; B Cell Proliferation; B-Cell Development; B-Lymphocytes; Beryllium; Binding; Bypass; Cataloging; Catalogs; Cells; Collection; Complex; Critical Pathways; Data; Development; Diagnostic; Disease; Disease Progression; Elements; Genes; Genetic; Growth; Health; Human; Immune; Immune system; Indium; Knowledge; Lesion; Leukocytes; Link; Lymphocyte; Lymphocyte Activation; Lymphocyte Function; Lymphoid; Lymphoma; Lymphomagenesis; Malignant Neoplasms; Mammalian Cell; Molecular; Molecular Diagnosis; Molecular Target; Mus; Mutation; Normal tissue morphology; Oncogenic; Pathway interactions; Patients; Physiology; Process; Proteins; Receptor Cell; Receptor Signaling; Receptors, Antigen, B-Cell; Recruitment Activity; Regulation; Role; Sampling; Scaffolding Protein; Signal Transduction; Signaling Molecule; Signaling Protein; T-Cell Receptor; T-Lymphocyte; Testing; Therapeutic; Ubiquitination; Variant; Work; adaptive immunity; base; cell behavior; cofactor; design; gain of function; innovation; insight; large cell Diffuse non-Hodgkin' s lymphoma; leukemia/lymphoma; loss of function; mutant; new therapeutic target; novel; novel diagnostics; overexpression; pathogen; protein function; receptor; scaffold; therapy design; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Antigen receptor signaling to NF-κB is a highly regulated, critical pathway for B and T lymphocyte activation during the adaptive immune response. NF-κB controls many genes required for lymphocyte function including genes that promote proliferation and survival. The inappropriate activation of NF-κB is associated with multiple leukemias and lymphomas, which frequently acquire mutations in signaling molecules that elicit their receptor- independent constitutive NF-κB activity. CARD11 (CARMA1) is a key scaffold protein that functions in both T cell receptor and B cell receptor pathways to transmit signals from the engaged receptor to the activation of the IKK complex and NF-κB. Aberrant CARD11-dependent signaling is required for the dysregulated proliferation of the activated B cell-like (ABC) subtype of Diffuse Large B Cell Lymphoma (DLBCL), and mutations in CARD11, which hyperactivate the protein, are found in ~10% of patient samples of ABC DLBCL. Previous work has established that during normal signaling, CARD11 undergoes a transition from an inactive to an active signaling scaffold that recruits several signaling cofactors into a complex that induces IKK activity. An Inhibitory Domain (ID) in CARD11 controls this transition; it keeps CARD11 inactive in the basal state, but receives signals from the engaged receptor that neutralize its inhibitory action and allow CARD11 to signal. However, it remains poorly understood how activated CARD11 signals to NF-κB, how precisely the ID functions, how lymphoma-associated mutations hyperactivate CARD11, and how aberrant CARD11 signaling causes disease. In this application, we will 1) characterize a novel collection of gain-of-function and loss-of- function CARD11 variants to define critical mechanisms of normal and oncogenic CARD11 signaling; 2) determine the mechanistic basis for how the Inhibitory Domain of CARD11 governs signal-dependent CARD11 activation; 3) test the hypothesis that hyperactive CARD11 is sufficient to alter B cell development and promote unwarranted B cell proliferation; and 4) characterize novel CARD11 signaling cofactors that we have recently identified. Our studies will help illuminate how signaling proteins, especially scaffolds, employ autoinhibitory mechanisms to allow their signal-induced activation, and how cancers exploit these mechanisms by selecting for mutations that bypass regulation to promote proliferation and survival. In addition, our results are likely to provide a catalogue of mutations that could underle the development of lymphomas in humans and therefore offer novel diagnostic insight and opportunities. Finally, our studies should reveal previously unrecognized molecular targets for the development of new therapies designed to treat NF-κB-dependent cancers and other diseases that result from aberrant immune cell behavior.

描述（由申请方提供）：抗原受体信号传导至NF-κB是适应性免疫应答期间B和T淋巴细胞活化的高度调节的关键途径。NF-κB控制淋巴细胞功能所需的许多基因，包括促进增殖和存活的基因。NF-κB的不适当活化与多发性白血病和淋巴瘤相关，其经常获得引起其受体非依赖性组成型NF-κB活性的信号分子突变。CARD 11（CARMA 1）是一种关键的支架蛋白，在T细胞受体和B细胞受体途径中发挥作用，将信号从接合受体传递到IKK复合物和NF-κB的活化。弥漫性大B细胞淋巴瘤（DLBCL）的活化B细胞样（ABC）亚型的增殖失调需要异常的CARD 11依赖性信号传导，并且在约10%的ABC DLBCL患者样本中发现了过度激活该蛋白的CARD 11突变。先前的工作已经确定，在正常信号传导过程中，CARD 11经历了从非活性信号传导支架到活性信号传导支架的转变，将几种信号传导辅因子招募到诱导IKK活性的复合物中。CARD 11中的抑制结构域（ID）控制这种转变;它使CARD 11在基础状态下保持不活动，但从参与的受体接收信号，中和其抑制作用并允许CARD 11发出信号。然而，对于活化的CARD 11如何向NF-κB信号传导、ID如何精确地发挥作用、淋巴瘤相关突变如何过度活化CARD 11以及异常的CARD 11信号传导如何导致疾病仍然知之甚少。在这个应用中，我们将1）描述一个新的功能增益集合 和功能丧失的CARD 11变体，以确定正常和致癌CARD 11信号传导的关键机制; 2）确定CARD 11的抑制结构域如何控制信号依赖性CARD 11活化的机制基础; 3）测试过度活化的CARD 11足以改变B细胞发育并促进不必要的B细胞增殖的假设;和4）表征我们最近鉴定的新型CARD 11信号传导辅因子。我们的研究将有助于阐明信号蛋白，特别是支架，如何采用自抑制机制来允许其信号诱导的激活，以及癌症如何通过选择绕过调节的突变来利用这些机制来促进增殖和存活。此外，我们的研究结果可能提供一个突变目录，这些突变可能是人类淋巴瘤发展的基础，因此提供了新的诊断见解和机会。最后，我们的研究应该揭示以前未被识别的分子靶点，用于开发新的治疗方法，用于治疗NF-κ B依赖性癌症和其他由异常免疫细胞行为引起的疾病。