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

基本信息

批准号：
9056446
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
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-07-19 至 2018-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9056446
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 TP53 gene Testing Therapeutic Ubiquitination Variant Work adaptive immunity base cell behavior cofactor design gain of function innovation insight large cell Diffuse non-Hodgkin&apos s lymphoma leukemia/lymphoma loss of function mutant new therapeutic target novel novel diagnostics novel therapeutics overexpression pathogen protein function receptor scaffold therapy design ubiquitin-protein ligase

项目摘要

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（由适用提供）：对NF-κB的抗原受体信号传导是自适应免疫响应期间B和T淋巴细胞激活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的不当激活与多个白血病和淋巴瘤有关，这些白血病和淋巴瘤经常在信号分子中获取突变，从而引起其受体独立的NF-κB活性。 Card11（Carma1）是一种关键支架蛋白，在T细胞受体和B细胞受体途径中起作用，以从参与受体传输信号到IKK复合物和NF-κB的激活。对于弥漫性大B细胞淋巴瘤（DLBCL）的活化B细胞样（ABC）亚型的扩散需要异常的Card11依赖性信号传导，Card11中的突变（DLBCL）过度激活蛋白质，在〜10％的ABC DLBCL的患者样本中发现了蛋白质过度激活的蛋白质。先前的工作已经确定，在正常信号传导期间，Card11经历了从无活动的非活动信号脚手架的过渡，该信号传导支架将几个信号辅因子募集到诱导IKK活性的复合物中。 Card11中的抑制域（ID）控制此过渡；它使Card11处于基本状态，但接收到接收器的信号，以中和其抑制作用并允许Card11发出信号。然而，它仍然鲜为人知的是如何激活的Card11信号向NF-κB信号，ID的确切功能，与淋巴瘤相关的突变如何过度激活Card11以及异常Card11信号引起疾病。在此应用中，我们将1）表征新的功能收集以及功能丧失Card11变体，以定义正常和致癌Card11信号的关键机制； 2）确定Card11抑制域如何控制信号依赖性Card11激活的机械基础； 3）检验假设，即多活跃Card11足以改变B细胞的发育并促进无理的B细胞增殖； 4）表征我们最近确定的新颖Card11信号辅助因子。我们的研究将有助于阐明信号蛋白，尤其是脚手架，员工自身抑制性机制如何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促进增殖和存活的突变来利用这些机制。此外，我们的结果可能会提供突变的目录，这些突变可能会影响人类淋巴瘤的发展，因此提供了新颖的诊断见解和机会。最后，我们的研究应揭示以前未识别的分子靶标，以开发旨在治疗异常免疫细胞行为引起的NF-κB依赖性癌症和其他疾病的新疗法。