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(申请人提供)：抗原受体信号传导至核因子-κB是获得性免疫反应中B和T淋巴细胞激活的一条高度受调控的关键途径。核因子-κB控制许多淋巴细胞功能所需的基因，包括促进增殖和存活的基因。NF-κB的不适当激活与多发性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上发生突变，从而引发其受体非依赖性的结构性NF-κB活性。CARD11(CARMA1)是T细胞受体和B细胞受体途径中的一种关键的支架蛋白，在激活的B细胞样弥漫性大B细胞淋巴瘤(DLBCL)的异常增殖中需要依赖于CARD11的信号转导信号。在ABC DLBCL患者中，约10%的患者样本中发现了CARD11基因的高激活突变。以前的工作已经证实，在正常的信号转导过程中，CARD11经历了从不活跃到活跃的信号支架的转变，该支架招募了几个信号辅助因子到一个诱导IKK活性的复合体中。CARD11中的抑制域(ID)控制着这一转变；它使CARD11在基础状态下保持不活跃，但从参与的受体接收信号，中和其抑制作用，并允许CARD11发出信号。然而，人们仍然不太清楚激活的CARD11是如何向NF-κB传递信号的，ID是如何准确发挥作用的，淋巴瘤相关的突变是如何激活CARD11的，以及CARD11信号的异常如何导致疾病。在本申请中，我们将1)描述一种新函数增益集合 CARD11和功能丧失的CARD11变体，以定义正常和致癌的CARD11信号的关键机制；2)确定CARD11的抑制结构域如何调控信号依赖的CARD11激活的机制基础；3)检验过度活跃的CARD11足以改变B细胞发育和促进B细胞过度增殖的假说；以及4)表征我们最近发现的新的CARD11信号辅助因子。我们的研究将有助于阐明信号蛋白，特别是支架，如何利用自动抑制机制来允许它们的信号诱导激活，以及癌症如何通过选择绕过调控的突变来促进增殖和生存。此外，我们的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知的分子靶点，用于开发新的治疗方法，旨在治疗NF-κB依赖的癌症和其他由异常免疫细胞行为引起的疾病。