Mechanisms of Control of Lymphocyte Activation and Proliferation by a Critical Signaling Integrator

项目概要/摘要 抗原受体信号传导至NF-κ B是B和T淋巴细胞活化的高度调节的关键途径 在适应性免疫反应期间。NF-κ 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-κ B的不适当激活与多种 淋巴瘤，这经常获得突变的信号分子，引发他们的受体非依赖性 组成型NF-κ B活性。CARD 11是一种在T细胞受体和B细胞中发挥作用的关键支架蛋白 受体通路将信号从接合受体传递到IKK复合物和NF-κ B的激活。 κ B。异常的CARD 11依赖性信号传导是活化的B细胞增殖失调所必需的。 弥漫性大B细胞淋巴瘤（DLBCL）的ABC样亚型，以及CARD 11的突变， 在约10%的ABC DLBCL患者样本中发现了过度激活蛋白质。以前的工作已经建立了 在正常信号传导过程中，CARD 11经历了从非活性到活性信号传导支架的转变， 它将几种信号辅因子募集到一个诱导IKK活性的复合物中。一个抑制结构域（ID）， CARD 11控制这种转换;它使CARD 11在基础状态下保持不活动，但从 参与受体，中和其抑制作用，并允许CARD11信号。淋巴瘤相关 CARD 11中的突变绕过正常激活并将CARD 11转化为组成型活性信号传导 脚手架然而，在正常抗原受体信号传导过程中，CARD 11是如何被激活的仍然知之甚少。 CARD 11的正常和致癌形式如何精确地向IKK复合体发出信号 激活NF-κ B，以及DLBCL相关的功能获得性CARD 11等位基因如何实现 正常的B细胞转化为淋巴瘤。在这个应用程序中，我们将1）调查如何信号潜力和合作 突变决定致癌CARD 11介导的体内异常B细胞增殖的程度; 2） 研究新鉴定的CARD 11活性所需的因子在正常和致癌抗原中的作用 受体信号传导;和3）剖析CARD 11信号传导循环中几个步骤所需的决定簇。我们 这些研究将促进对淋巴细胞增殖过程中抗原受体信号传导机制的理解。 激活，阐明信号蛋白，特别是支架，如何实现信号诱导的激活过程中， 正常的生理行为，并提高我们对如何发现遗传病变的组合的理解 决定了疾病的严重程度。我们的研究应该揭示了一种以前未被发现的分子 开发新疗法的目标，旨在治疗NF-κ B依赖性癌症和其他疾病 免疫细胞行为异常引起的

PROJECT SUMMARY/ABSTRACT 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 lymphomas, which frequently acquire mutations in signaling molecules that elicit their receptor-independent constitutive NF-κB activity. CARD11 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. Lymphoma-associated mutations in CARD11 bypass normal activation and convert CARD11 into a constitutively active signaling scaffold. However, it remains poorly understood how during normal antigen receptor signaling CARD11 is converted to its active state, how precisely normal and oncogenic forms of CARD11 signal to the IKK complex to activate NF-κB, and how DLBCL-associated gain-of-function CARD11 alleles achieve the transformation of normal B cells into lymphoma. In this application we will 1) investigate how signaling potential and cooperating mutations determine the extent of oncogenic CARD11-mediated aberrant B cell proliferation in vivo; 2) investigate the role of a newly identified factor required for CARD11 activity in normal and oncogenic antigen receptor signaling; and 3) dissect determinants required for several steps in the CARD11 signaling cycle. Our studies will advance understanding of the mechanisms of antigen receptor signaling during lymphocyte activation, illuminate how signaling proteins, especially scaffolds, achieve signal-induced activation during normal physiological behavior, and improve our understanding of how the combination of genetic lesions found in lymphoma determines disease severity. Our studies should reveal a previously unrecognized molecular target for the development of new therapies designed to treat NF-κB-dependent cancers and other diseases that result from aberrant immune cell behavior.