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：
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
项目类别：
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&apos 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

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（由申请人提供）：对NF-κB的抗原受体信号传导是一个高度构成的环，NF-κB控制着淋巴细胞功能所需的许多人。通过白血病和淋巴瘤无关，可以引起其受体独立的征服NF-κB活性（CARMA1）。在约10％的患者样本中，在正常信号传导过程中发现，在正常的患者样本中发现了激活的B细胞样（ABC）亚型（DLBCL）的弥漫性大B细胞淋巴瘤（DLBCL）的突变（DLBCL）。 Card11从一个不活跃的脚手架上进行过渡。向NF-κB的信号，ID的精确功能，与淋巴瘤相关的突变如何过度激活Card11以及在此应用中引起疾病的异常。和功能的损失Card11变体定义了正常的致癌Card11信号的关键机制； THATENTLY EE HAVENTLY Our Studies Will Hell How Signaling Proteins, Especially Scaffolds, EMPLOY AUTOINHIBITORY MECHANISMS TO ALLOW THEIR SIGNAR-IIR D Activation, and How Cancers Exploit THATITING FOR MUTASSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSSS SULIFERATION some SURVIVAL. Ely to Provide a Catalogue of Muterle Underle The Development of Lymphomas in人类，因此提供了诊断性的洞察力。