New mechanisms for modulating the MALT1 oncoprotein

项目总结： 淋巴瘤是美国第六种最常见的癌症，估计有23%的人会受到影响 10万人。虽然在我们对淋巴瘤生物学和 我们提供治疗的能力，许多淋巴瘤患者继续遭受不良预后 美国每年约有2万人死于淋巴瘤。诊断的新方法 以及淋巴瘤的治疗是当务之急。 这一应用的重点是阐明调节MALT1的分子机制，MALT1是一种重要的 B细胞淋巴瘤中的癌蛋白。MALT1是一种细胞质蛋白，用于介导抗原受体- 依赖淋巴细胞的激活、增殖和存活，通过刺激典型的促生存的NF-κB 转录因子。在B淋巴细胞中，抗原受体被称为B细胞受体(BCR)。在这些 细胞，bcr诱导的，依赖MALT1的NF-κB激活是正常适应过程中的必需事件 免疫反应，但这一途径的异常激活可导致淋巴瘤。的确，基因分析 已发现在特定亚型的B细胞淋巴瘤中，恶性B细胞劫持了BCR信号通路 以促进自身的成长和生存。 BCR刺激导致CARMA1-Bcl10-MALT1(CBM)蛋白信号复合体的组装， 其中MALT1通过执行两个重要功能作为效应器。首先，MALT1充当了一个脚手架 来招募和激活下游的信号蛋白，第二，MALT1作为一种蛋白酶来切割 特定底物信号转导蛋白并改变其活性。实现适当目标的关键重要性 MALT1活性的调节表现为bcr亚基或bcr亚基的功能增益突变。 CARMA1导致MALT1活性被夸大，在人类B细胞淋巴瘤中反复检测到。因此， Malt1是B淋巴瘤的关键调控因子，也是一种很有前途的新基因，受到了广泛的研究 药物抑制的目标。 这一提议调查了特定蛋白质能够控制的创新假设。 MALT1的功能，因此它们在某些亚型B细胞淋巴瘤中的缺失可能与MALT1的异常有关 活动。功能获得型BCR或CARMA1突变体的存在可能与这些蛋白质的丢失协同作用 在促进淋巴肿大方面；相反，丢失本身可能是致病的。我们这项提案的目标是 阐明特定的蛋白质-蛋白质相互作用可以消除MALT1的分子基础 活性，以确定这种相互作用如何影响淋巴细胞的生长和存活，并利用这一点 为设计MALT1依赖的淋巴瘤的新治疗方法提供信息。

PROJECT SUMMARY: Lymphoma is the sixth most common form of cancer in the United States, affecting an estimated 23 per 100,000 people. While there have been significant advances in our understanding of lymphoma biology and our ability to provide curative therapy, many patients with lymphoma continue to suffer poor outcomes with approximately 20,000 people dying from lymphoma in the US each year. Novel approaches to the diagnosis and treatment of lymphoma are urgently needed. This application is focused on elucidating the molecular mechanisms that regulate MALT1, a central oncoprotein in B-cell lymphoma. MALT1 is a cytoplasmic protein that serves to mediate antigen receptor- dependent lymphocyte activation, proliferation and survival, via stimulation of the canonical pro-survival NF-κB transcription factor. In B-lymphocytes, the antigen receptor is known as the B-cell receptor (BCR). In these cells, BCR-induced, MALT1-dependent NF-κB activation is a required event during the normal adaptive immune response, but dysregulated activation of this pathway can lead to lymphoma. Indeed, genetic analysis has revealed that in specific subtypes of B-cell lymphoma, malignant B cells highjack BCR signaling pathways in order to promote their own growth and survival. BCR stimulation results in assembly of the CARMA1-Bcl10-MALT1 (CBM) protein signaling complex, where MALT1 serves as the effector by carrying out two important functions. First, MALT1 acts as a scaffold to recruit and activate downstream signaling proteins, and second, MALT1 acts as a protease to cleave specific substrate signaling proteins and alter their activities. The critical importance of achieving appropriate regulation of MALT1 activity is demonstrated by the fact that gain-of-function mutations in BCR subunits or in CARMA1, resulting in exaggerated MALT1 activity, are recurrently detected in human B-cell lymphoma. Thus, MALT1 is the subject of intense investigation as a key regulator of B-lymphomagenesis and a promising new target for pharmaceutical inhibition. This proposal investigates the innovative hypothesis that specific proteins are capable of controlling MALT1 function, such that their loss in some subtypes of B-cell lymphoma may contribute to aberrant MALT1 activity. The presence of gain-of-function BCR or CARMA1 mutants may synergize with loss of such proteins in promoting lymphomagenesis; conversely, loss alone may be pathogenic. Our goals for this proposal are to elucidate the molecular underpinnings by which specific protein-protein interactions can abrogate MALT1 activity, to determine how this interaction influences lymphocyte growth and survival, and to utilize this information to inform the design of novel therapeutic approaches to MALT1-dependent lymphoma.