POSTTRANSLATIONAL MODIFICATION OF RASGRP1 PROTEIN IN T LYMPHOCYTES

T 淋巴细胞中 RASGRP1 蛋白的翻译后修饰

• 批准号: 8169807
• 负责人: JEROEN ROOSE
• 金额: $ 0.71万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-12 至 2011-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8169807
• 关键词: Acute Lymphocytic Leukemia; Antigen Receptors; Blood; Bone Marrow Cells; Cancerous; Cell Surface Receptors; Cells; Computer Retrieval of Information on Scientific Projects Database; Event; Funding; Grant; Growth; Institution; Leukocytes; Lymphocyte; Malignant Neoplasms; Mass Spectrum Analysis; Mus; Mutate; Mutation; Oncogene Proteins; Patients; Post-Translational Protein Processing; Proteins; Research; Research Personnel; Resources; Sampling; Signal Transduction; Signaling Protein; Site; Skin Carcinoma; Source; T-Cell Receptor; T-Lymphocyte; Thymoma; Transcript; United States National Institutes of Health; Work; insight; leukemia/lymphoma; lymphocyte proliferation; overexpression; prevent; ras Guanine Nucleotide Exchange Factors; ras Proteins; receptor binding; research study

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. T cell acute lymphoblastic leukemia/lymphoma (TALL/L) involves abnormal proliferation of lymphocytes, or white blood cells. TALL/L patients often show elevated levels of the active form of the oncoprotein, RasGTP, in blood and bone marrow cells. In contrast to other cancers, few of these TALL/L patients have the typical mutations in Ras protein that would explain this accumulation. This finding suggests that many TALL/L patients have abnormal expression or activity of signaling proteins upstream of RasGTP. Lymphocytes express two Ras guanine nucleotide exchange factors (RasGEFs), SOS and RasGRP1, which work together to activate Ras when cell surface receptors are stimulated. Previous work demostrated that RasGRP1 is the dominant RasGEF in lymphocytes after antigen receptor stimulation. Mice overexpressing wild type RasGRP1 develop thymomas and skin carcinomas. Thus non-cancerous cells must have a mechanism to limit RasGRP1 function. Surprisingly, the negative regulatory factors that turn off this strong, RasGRP1-driven growth signal and prevent uncontrolled proliferation are unknown. Control of signals received via receptor binding can occur through posttranslational modification of signaling components. Decreases in RasGRP1 protein level after T cell receptor (TCR) stimulation precedes RasGRP1 transcript degradation. This study will identify the posttranslational modification events controlling RasGRP1 protein levels and activity within lymphocytes. The proposed experiments will use Mass Spectrometry to examine posttranslational modification events that occur on RasGRP1 protein following TCR stimulation. Modified sites identifed will give us insight into the control of RasGRP1 activity in normal lymphocytes and provide mechanistic clues for TALL/L patient samples with mutated forms of RasGRP1.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 T细胞急性淋巴细胞白血病/淋巴瘤（TALL/L）涉及淋巴细胞或白色血细胞的异常增殖。 TALL/L患者通常在血液和骨髓细胞中表现出癌蛋白活性形式RasGTP水平升高。 与其他癌症相比，这些TALL/L患者中很少有Ras蛋白的典型突变可以解释这种积累。 这一发现表明，许多TALL/L患者存在RasGTP上游信号蛋白的异常表达或活性。 淋巴细胞表达两种Ras鸟嘌呤核苷酸交换因子（RasGEFs），SOS和RasGRP 1，当细胞表面受体受到刺激时，它们共同作用以激活Ras。 以前的工作证明，RasGRP 1是抗原受体刺激后淋巴细胞中的主要RasGEF。 过表达野生型RasGRP 1的小鼠发生胸腺瘤和皮肤癌。 因此，非癌细胞必须具有限制RasGRP 1功能的机制。 令人惊讶的是，关闭这种强大的RasGRP 1驱动的生长信号并防止不受控制的增殖的负调控因素是未知的。 通过受体结合接收的信号的控制可以通过信号传导组分的翻译后修饰发生。 T细胞受体（TCR）刺激后RasGRP 1蛋白水平的降低先于RasGRP 1转录物降解。 本研究将确定翻译后修饰事件控制淋巴细胞内RasGRP 1蛋白水平和活性。 拟议的实验将使用质谱法来检查TCR刺激后RasGRP 1蛋白上发生的翻译后修饰事件。 经鉴定的修饰位点将使我们深入了解正常淋巴细胞中RasGRP 1活性的控制，并为具有RasGRP 1突变形式的TALL/L患者样本提供机制线索。