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: 8704412
• 负责人: Joel L Pomerantz
• 金额: $ 32.61万
• 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 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8704412
• 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; Human; Immune; Immune response; 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; 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; public health relevance; receptor; scaffold; therapy design; ubiquitin-protein ligase

DESCRIPTION (provided by applicant): Antigen receptor signaling to NF-?B is a highly regulated, critical pathway for B and T lymphocyte activation during the adaptive immune response. NF-?B controls many genes required for lymphocyte function including genes that promote proliferation and survival. The inappropriate activation of NF-?B is associated with multiple leukemias and lymphomas, which frequently acquire mutations in signaling molecules that elicit their receptor- independent constitutive NF-?B 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-?B. 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-?B, 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-?B-dependent cancers and other diseases that result from aberrant immune cell behavior.

描述（由申请人提供）：抗原受体向NF-？B是一个高度调控的，在适应性免疫反应中B和T淋巴细胞活化的关键途径。NF - ?B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-?的不当激活B与多发性白血病和淋巴瘤有关，这两种疾病在信号分子中经常发生突变，从而引发与受体无关的构成性NF-？B的活动。CARD11 （CARMA1）是一个关键的支架蛋白，在T细胞受体和B细胞受体途径中发挥作用，将信号从参与受体传递到IKK复合物和NF- B的激活。漫漫性大B细胞淋巴瘤（DLBCL）活化的B细胞样（ABC）亚型的增殖失调需要异常的CARD11依赖信号，并且在约10%的ABC DLBCL患者样本中发现了CARD11突变，该突变使该蛋白过度激活。先前的研究已经证实，在正常的信号传导过程中，CARD11经历了从一个不活跃的信号传导支架到一个活跃的信号传导支架的转变，它将几个信号传导辅助因子招募到一个诱导IKK活性的复合体中。CARD11中的抑制结构域（ID）控制着这种转变；它使CARD11在基础状态下保持非活性，但接收来自参与受体的信号，该受体中和其抑制作用并允许CARD11发出信号。然而，对于激活CARD11如何向NF-？B， ID如何精确地起作用，淋巴瘤相关突变如何过度激活CARD11，以及异常的CARD11信号如何导致疾病。在这个应用程序中，我们将1)描述一个新的功能增益集合